Curr. Med. Chem. [JOURNAL]
Sun
200 papers
LncRNA signature associated with amino acid metabolism: A novel prognostic tool for Clear Cell Renal Cell Carcinoma.
Lin C, Huang B, Fan C … +3 more , He S, Zheng J, Li Y
Curr Med Chem · 2026 Jul · PMID 42393887 · Publisher ↗
The progression of clear cell renal cell carcinoma (ccRCC) is influenced by amino acid metabolism (AAM) and long non-coding RNAs (lncRNAs). However, the prognostic significance of AAM-related lncRNAs (AAMLRs) in ccRCC re...
The progression of clear cell renal cell carcinoma (ccRCC) is influenced by amino acid metabolism (AAM) and long non-coding RNAs (lncRNAs). However, the prognostic significance of AAM-related lncRNAs (AAMLRs) in ccRCC remains to be further investigated. The AAMLRs signature were constructed via univariate Cox and LASSO analyses, which was validated in a local cohort. Herein, we found that patients with low risk scores showed longer survival time than those with high risk scores. Several immune checkpoints were upregulated in the patients classified as high-risk group. Differences were observed between the high- and low-risk groups in terms of immune cell subtypes, including CD8+ T cells, macrophages, and NK cells. High-risk patients showed increased drug sensitivity towards 5-fluorouracil, paclitaxel, vorinostat, sorafenib, and cisplatin. In conclusion, we demonstrated that the prognostic AAMLRs signature acts as a prognostic predictor in ccRCC and provide novel insights into treatment.
HRI Kinase Modulation by BTdCPU as a Therapeutic Strategy for Bortezomib Resistance in Prostate Cancer.
Seker S, Okur E, Yerlikaya A
Curr Med Chem · 2026 Jul · PMID 42393886 · Publisher ↗
BACKGROUND: Heme-Regulated Inhibitor (HRI) kinase is a key serine-threonine kinase that regulates eIF2α phosphorylation and Integrated Stress Signaling (ISR). The present study used parental and bortezomib-resistant PC3...
BACKGROUND: Heme-Regulated Inhibitor (HRI) kinase is a key serine-threonine kinase that regulates eIF2α phosphorylation and Integrated Stress Signaling (ISR). The present study used parental and bortezomib-resistant PC3 prostate cancer cells to examine whether pharmacologic modulation of this pathway, particularly with BTdCPU, retains activity in a resistant setting and how it relates to stress-signaling markers. MATERIALS AND METHODS: We initially assessed the cytotoxic effects of the HRI activator BTdCPU, along with its inhibitors hemin and ZnPP, in bortezomib-resistant cells using the MTT assay. A single BTdCPU + bortezomib concentration pair was then examined using the real-time iCELLigence system and AO/EB morphology. Western blotting was performed to evaluate total HRI, phosphorylated eIF2, Hsp70, Hsp60, and polyubiquitin (PolyUb) conjugates. Public-dataset analyses were used to provide descriptive clinical context. RESULTS: The IC50 values for bortezomib in parental and resistant cells were 44.34 nM and 1.151 µM, respectively, indicating that the resistant cells were approximately 26 times more resistant to bortezomib than the parental cells. The IC50 of BTdCPU in parental and resistant cells was found to be 1.268 µM and 1.971 µM, respectively. Notably, BTdCPU-induced HRI activation appears to act through a mechanism distinct from classical proteasome inhibition, as it promotes eIF2α phosphorylation independently of stress markers such as Hsp70 and polyubiquitin (PolyUb) conjugate accumulation, which are observed in parental cells treated with bortezomib, but not in resistant cells treated similarly. Descriptive bioinformatic analyses also indicated differential HRI expression across prostate cancer subgroups and according to TP53 status. DISCUSSION: The current findings suggest that cancer cell resistance may, in part, arise from the overactivation of the HRI/eIF2α signaling pathway, which is likely triggered by the increased expression of PolyUb conjugates and Hsp70. These findings support further investigation of HRI/ISR-related signaling in proteasome-inhibitor resistance; however, the present data are pharmacologic and associative rather than causal, and they do not establish direct HRI dependence or downstream ISR effector involvement. CONCLUSION: The findings indicate that BTdCPU, either alone or in combination with bortezomib, warrants further investigation as a potential strategy for overcoming bortezomib resistance in both p53-wild type and p53-mutant cancer cells.
EGFR Dysregulation in Cancer: From Molecular Mechanisms and Key Mutations to Evolving TKI Strategies and Resistance Mitigation.
Tamimi A, Khan M, Khan MKA … +1 more , Akhtar S
Curr Med Chem · 2026 Jul · PMID 42393885 · Publisher ↗
INTRODUCTION/OBJECTIVE: Regulation of cell growth, survival, and differentiation relies heavily on the epidermal growth factor receptor (EGFR). Dysregulations of EGFR signaling, whether due to overexpression or mutations...
INTRODUCTION/OBJECTIVE: Regulation of cell growth, survival, and differentiation relies heavily on the epidermal growth factor receptor (EGFR). Dysregulations of EGFR signaling, whether due to overexpression or mutations, play a major role in the development of many cancers, particularly non-small cell lung cancer. In this review, we provide a comprehensive overview of EGFR biology, its signaling pathways, and strategies for therapeutic targeting. METHODS: This review combines the existing research on EGFR structure and its interactions with ligands, along with the signaling pathways that follow. It focuses on RAS/RAF/MEK/ERK and PI3K/AKT/mTOR axes, while considering JAK/STAT and PLCγ/PKC signaling. It alsofocuses on the triple mutant EGFR (L858R, T790M, and C797S) and discusses the therapeutic shift from first-generation reversible inhibitors to later generations of irreversible tyrosine kinase inhibitors. This review also examines a new wave of treatments. It explores fourth-generation TKIs and allosteric inhibitors alongside newer treatment strategies, such as PROTACs, combination immunotherapy, and precision medicine methods. RESULTS: For NSCLS patients with activating mutations, progress in EGFR-targeted treatments has transformed clinical outcomes. Due to the rise in resistance mechanisms, such as secondary mutations, the long-term effectiveness remains blocked. However, ongoing research on new treatment strategies reveals promising potential to overcome resistance and improve treatment effectiveness. DISCUSSION: Combining what we have learned about the EGFR at the molecular level with new therapeutic approaches highlights how valuable precision oncology has become in treating cancer. To improve treatment outcomes, we need to understand how pathways, mutations, and drug response interact with each other. CONCLUSION: In this review, we aim to outline current knowledge and future directions in EGFR-targeted therapy by providing insights into newer strategies and precision oncology.
DHRS2 as a Novel Thalidomide Target Regulating Mitophagy and Inflammation in Head and Neck Squamous Cell Carcinoma.
Wu Y, Yao Q, Li Y … +4 more , Song Z, Gan M, Zhong J, Liang L
Curr Med Chem · 2026 Jul · PMID 42393884 · Publisher ↗
BACKGROUND: Radiation Therapy (RT) in Head and Neck Squamous Cell Carcinoma (HNSCC) often induces inflammation. Here, we examined the relationship between mitophagy and inflammation in HNSCC. METHODS: The Cancer Genome A...
BACKGROUND: Radiation Therapy (RT) in Head and Neck Squamous Cell Carcinoma (HNSCC) often induces inflammation. Here, we examined the relationship between mitophagy and inflammation in HNSCC. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus were analyzed to identify genes associated with HNSCC, mitophagy, inflammation, and Thalidomide (THD). Differentially Expressed Genes (DEGs) were evaluated for functional enrichment. A prognostic model was constructed using LASSO and COX regression and evaluated using Kaplan-Meier analysis. Based on its reported role in alleviating Radiation-Induced Oral Mucositis (RIOM) and inflammation, THD was assessed using molecular docking to further investigate its potential mechanism. Knockdown cell lines were generated to examine the function of dehydrogenase/reductase 2 (DHRS2). RESULTS: In total, 535 related genes were identified, and a 26-gene prognostic model was established, effectively stratifying patients into high- and low-risk groups (AUC: 0.7-0.9). DHRS2 was identified as a key gene of interest, with molecular docking indicating strong binding affinity to THD. in vitro, DHRS2 knockdown significantly inhibited HNSCC cell proliferation, migration, and invasion while promoting apoptosis (p<0.05). THD reduced DHRS2 expression and increased PINK1/Parkin-related mitophagy. DISCUSSION: These findings suggest that dysregulation of mitophagy and inflammation contributes to HNSCC progression and may underlie radiation-induced inflammatory injury. DHRS2 was identified as a potential THD-responsive target, linking bioinformatics findings with pharmacological intervention. These findings also provide a basis for exploring therapeutic strategies targeting mitophagy and inflammation in HNSCC. CONCLUSION: We developed a prognostic model based on mitophagy- and inflammation-related genes in HNSCC and identified DHRS2 as a potential THD target. These results highlight the interplay between mitophagy and inflammation in HNSCC, offering insights for the prognosis and management of inflammation.
Synthetic AtMP2 from Anabas testudineus: Comprehensive ADMET and In Vivo Toxicity Assessment to Enable Future Therapeutic Development.
Mohd Noordin MA, Najm AA, Huei Wern L … +3 more , Eziwar Dyari HR, Law D, Fazry S
Curr Med Chem · 2026 Jul · PMID 42393883 · Publisher ↗
BACKGROUND/OBJECTIVES: Breast cancer remains one of the common causes of cancer mortality globally, and the development of safe and selective anticancer agents remains an important research priority. AtMP2, a synthetic p...
BACKGROUND/OBJECTIVES: Breast cancer remains one of the common causes of cancer mortality globally, and the development of safe and selective anticancer agents remains an important research priority. AtMP2, a synthetic peptide derived from the mucus of climbing perch (Anabas testudineus), has previously demonstrated anticancer activity against breast cancer cell lines. However, its pharmacokinetic properties and in vivo safety profile have not been comprehensively evaluated. Therefore, this study aimed to investigate the ADMET-related characteristics and preliminary in vivo safety of AtMP2 using integrated in silico, in vitro, and in vivo approaches. METHODS: The ADMET profile of AtMP2 was evaluated using in silico prediction (ADMETlab 2.0) and in vitro assays examining lipophilicity, plasma and microsomal protein binding, metabolic stability in human liver microsomes, and bidirectional permeability in MDCK and MDCK-MDR1 cell lines. Cytotoxicity against mammalian cells and antibacterial activity were also assessed. Acute and sub-acute toxicity studies were conducted in female BALB/c mice (n = 5 per group) following intravenous administration. RESULTS: AtMP2 was hydrophilic (logD = -0.86 ± 0.3), showed a high plasma unbound fraction (65.9%) and microsomal unbound fraction (91.4%), moderate metabolic stability (t1/2 = 136.53 ± 12.6 min), and moderate intrinsic clearance (10.86 ± 0.2 mL/min/kg). Permeability studies demonstrated measurable transport with moderate efflux via the P-glycoprotein efflux pump (efflux ratio = 2.43). AtMP2 was not cytotoxic to MDCK-MDR1 cells, retained antibacterial activity, and did not cause mortality, abnormal behaviour, significant body-weight changes, or histological evidence of organ damage at doses up to 15 mg/kg in mice. DISCUSSION/CONCLUSION: Collectively, these findings suggest that AtMP2 possesses encouraging preliminary ADMET-related and short-term tolerability characteristics for an early-stage peptide lead. The present study provides an initial preclinical assessment of AtMP2 and supports its continued investigation as a potential peptide-based therapeutic candidate. Nevertheless, further pharmacokinetic, biochemical safety, long-term tolerability, and efficacy studies remain necessary.
Screening of Medicinal and Edible Homology Substances for Diabetic Kidney Disease Based on GraphBAN.
Ning Y, Zhou X, Zhang L … +2 more , Wang G, Wang J
Curr Med Chem · 2026 Jun · PMID 42381320 · Publisher ↗
BACKGROUND: Diabetic kidney disease (DKD) is a critical microvascular complication of diabetes mellitus, and the current pharmacotherapies are limited by side effects. Medical and edible homology (MEH) Agents: The DKD an...
BACKGROUND: Diabetic kidney disease (DKD) is a critical microvascular complication of diabetes mellitus, and the current pharmacotherapies are limited by side effects. Medical and edible homology (MEH) Agents: The DKD and healthy control multi- -target active and low-toxic drugs (MEH) agents were identified based on transcriptomic data of DKD patients and healthy controls retrieved in the GEO database. METHODS: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and other databases were searched to obtain active components of 106 MEH substances. The GraphBAN model was used to predict the compound-target interaction and filter candidate components and genes based on the five rules proposed by Lipinski. A multi-level MEH-Ingredient-Gene-Pathway network was built to discover important active ingredients and hub genes. The protein-protein interaction (PPI) network analysis, immune cell infiltration analysis, molecular docking, and molecular dynamics simulations were further used to validate core interactions. RESULTS: A total of 436 DEGs were identified. Screening via the GraphBAN model generated 6 candidate active ingredients and 11 candidate genes, from which 5 key ingredients (aurantio-obtusin, obtusin, licoisoflavanone, triptolide, triptolidenol) and 3 core genes (CERS6, CETP, FYN) were determined. PPI network analysis suggested that these core genes synergistically regulate lipid metabolism and immune processes. Further evaluation revealed concurrent immune activation and suppression in DKD, with key genes negatively correlated with immune cell infiltration levels. Finally, molecular docking and dynamics simulations verified stable binding affinities of the corresponding complexes. DISCUSSION: The present study investigated the therapeutic potential of multi-target, low-toxicity MEH substances against DKD. Using transcriptomic profiling, compound-- target prediction, and regulatory network construction, we identified 5 key MEH ingredients and 3 core genes. These molecules may stabilize DKD progression via modulating lipid metabolism and immune-inflammatory pathways, providing a basis for the development of multi-target natural products and supporting the value of artificial intelligence in MEH-related research. CONCLUSION: In the current study, the authors examined the anti-DKD effects of MEH agents and identified 5 main ingredients and 3 central genes, which could prevent DKD due to the regulation of lipid metabolism. Some of the limitations, such as a rather limited sample size, must be taken up in future studies.
Berberine as an Antimicrobial Agent and Gut Microbiota Modulator: Mechanisms and Therapeutic Potential.
Chen J, Li X, Ou Y … +7 more , Hu Y, Chen Y, Xu F, Bai K, Yang Z, Yuan J, Niu H
Curr Med Chem · 2026 Jun · PMID 42381319 · Publisher ↗
Berberine exhibits remarkable antimicrobial properties against various pathogens, including bacteria, fungi and viruses. It has long been used to treat gastrointestinal disorders like diarrhea. Importantly, berberine exe...
Berberine exhibits remarkable antimicrobial properties against various pathogens, including bacteria, fungi and viruses. It has long been used to treat gastrointestinal disorders like diarrhea. Importantly, berberine exerts profound effects on the gut microbiota. The mechanisms of action are complex and diverse, including but not limited to modulating microbiota abundance and maintaining microbial homeostasis. Berberine can exert therapeutic effects by promoting intestinal production of short-chain fatty acids to enrich beneficial microbial populations, and it may also delay disease progression by inhibiting pathogenic bacteria. Furthermore, as one of the most relevant targets of berberine, the gut microbiota also regulate inflammation responses, metabolism, and immune regulation, playing a crucial role in human physiological and pathological processes. Notably, a growing number of berberine derivatives and nano-formulations are emerging as important innovative therapeutics and are playing a key role in advancing the development of natural medicines. However, the specific mechanism of action between berberine and microbiome is still unclear. This review discusses the mechanisms of action and therapeutic potential of berberine, its derivatives, and nanoformulations as antibacterial agents and gut microbiota modulators, aiming to provide more robust evidence for the clinical development and pharmaceutical translation of berberine, thereby achieving the goal of better disease treatment.
Research Progress of Grapefruit-derived Extracellular Vesicles in Anti-tumor Treatment.
Deng Y, Lin W, Li J … +4 more , Zhou Z, Yang T, Liu J, Jiang Y
Curr Med Chem · 2026 Jun · PMID 42381318 · Publisher ↗
To date, the application of chemotherapy and gene therapy has improved the effectiveness and survival period of cancer patients. However, cancer remains a leading cause of death worldwide. Researchers have recognized the...
To date, the application of chemotherapy and gene therapy has improved the effectiveness and survival period of cancer patients. However, cancer remains a leading cause of death worldwide. Researchers have recognized the internal limitations of chemotherapy and gene therapy in anti-tumor treatment. Therefore, developing safe and effective delivery vehicles is crucial for overcoming the limitations. A variety of lipidstructured nano-vesicles, ranging from synthetic liposomes to biomimetic vehicles and natural membrane vesicles derived from mammalian cells, have been utilized as drug delivery systems (DDS) in anti-tumor treatment. However, due to factors such as yield, cost, safety, and ethical considerations, researchers are actively seeking optimal delivery vehicles. In recent years, there has been a growing interest in the research and therapeutic applications of plant-derived vesicles in anti-tumor treatment. Some plant-derived vesicles are known to have anti-tumor properties due to their unique bioactive compounds, and they can also serve as delivery vehicles of anti-tumor agents (e.g., drugs, siRNA, and functional exogenous proteins). Grapefruits, in particular, contain several phytochemicals, such as bergamottin, hesperidin, and naringenin, which contribute to their anti-tumor properties. Grapefruit-derived extracellular vesicles (GEVs) and the vesicles reassembled from their total lipids have demonstrated promise as both anti-tumor agents and as delivery systems for chemotherapy drugs and therapeutic genes in cancer research. This review will introduce the characteristics and anti-tumor properties of GEVs and their reassembled vesicles, as well as the research progress in anti-tumor treatment. Finally, we will discuss the challenges and prospects of GEVs and their reassembled vesicles in anti-tumor treatment.
Corrigendum to: Neuroprotective Mechanisms of Oxygen and Ethanol: A Potential Combination Therapy in Stroke.
Parmar S, Moore-Langston S, Fredrickson V … +4 more , Kim JM, Rastogi R, Elmadhoun O, Ding Y
Curr Med Chem · 2026 Jun · PMID 42381317 · Publisher ↗
In the published version of this article [1], the author's name was incorrectly listed as "Omar Elmadoun." Subsequently, the author requested that the name be corrected to "Omar Elmadhoun" to reflect the preferred and ac...
In the published version of this article [1], the author's name was incorrectly listed as "Omar Elmadoun." Subsequently, the author requested that the name be corrected to "Omar Elmadhoun" to reflect the preferred and accurate spelling. This correction has been made at the author's request, and the original article has been updated accordingly. The original article can be found online at: https://www.eurekaselect.com/article/64535. The Publisher apologizes for any confusion or inconvenience caused.
Ferroptosis and Its Crosstalk with Other Cell Death Modes in Ischemic Stroke.
Zhu H, Zhou LI, Yu W … +1 more , Yang Q
Curr Med Chem · 2026 Jun · PMID 42381316 · Publisher ↗
Ischemic stroke is the most common cerebrovascular disease. The core pathological mechanism underlying its neurological deficits is the massive neuronal death triggered by cerebral ischemia, hypoxia, and reperfusion inju...
Ischemic stroke is the most common cerebrovascular disease. The core pathological mechanism underlying its neurological deficits is the massive neuronal death triggered by cerebral ischemia, hypoxia, and reperfusion injury following a sudden interruption of cerebral blood flow. Ferroptosis is a form of cell death characterized by iron overload, amino acid metabolism disorder, and lipid peroxidation, primarily occurring during organ ischemia-reperfusion. In recent years, with the clinical advancement of intravenous thrombolysis and endovascular thrombectomy, the incidence of ferroptosis in neurons after ischemic stroke has increased significantly. Importantly, substantial evidence indicates that ferroptosis not only directly damages neurons but also acts synergistically with other modes of cell death, further exacerbating brain tissue injury. Therefore, this review summarizes the mechanisms of ferroptosis following ischemic stroke, its role in neurological impairment, and explores the synergistic interactions between ferroptosis and other cell death pathways, which will provide an important theoretical foundation for the development of neuroprotective pharmacological therapies and innovative treatment strategies for ischemic stroke.
Integrative Analysis Reveals BPTF, COL1A1, and COL4A2 as Fibroblast-Related Biomarkers Associated with Immune Infiltration in Ovarian Cancer.
Wang H, Li Z, Xia J … +5 more , Li Z, Wen X, Xiong J, Zhao N, Huang R
Curr Med Chem · 2026 Jun · PMID 42381315 · Publisher ↗
INTRODUCTION: As fibroblasts constitute a crucial component of the tumor microenvironment (TME), identifying fibroblast-related genes may help elucidate the mechanisms underlying ovarian cancer (OC) progression. METHODS:...
INTRODUCTION: As fibroblasts constitute a crucial component of the tumor microenvironment (TME), identifying fibroblast-related genes may help elucidate the mechanisms underlying ovarian cancer (OC) progression. METHODS: The single-cell RNA-seq (scRNA-seq) data (GSE184880) and bulk transcriptomic data (GSE66957) for OC were obtained from the Gene Expression Omnibus (GEO) database. We then performed single-cell data analysis to analyze the infiltration profiles of cell subpopulations and applied CellChat to map their interaction networks. High-dimensional WGCNA (hdWGCNA) was used to screen module genes related to fibroblasts in OC. Key genes associated with both OC progression and fibroblasts, as potential biomarkers, were screened by LASSO. CIBERSORT analysis was conducted to analyze the relationship between the key genes and immune infiltration. RESULTS: Among the eight subpopulations identified in OC samples, cell-cell communication between T cells and fibroblasts was primarily mediated by CD99-CD99 and HLAC-KIR2DL3. Three key genes (BPTF, COL1A1, and COL4A2) were identified using hdWGCNA and LASSO. DISCUSSION: BPTF, COL1A1, and COL4A2 were identified as crucial fibroblast-related markers in OC. These genes may contribute to the tumor immune microenvironment and malignant progression of OC. However, their prognostic value and association with immunotherapy response require further validation in independent survival cohorts and treatment-response datasets. CONCLUSION: This study discovered three key fibroblast-related genes associated with OC progression and immune cell infiltration. These findings offer potential biomarkers and a theoretical foundation for the development of novel therapeutic strategies for OC.
Phenylalanine Hydroxylase as a Prognostic Marker in Pancreatic Cancer: Insights into Tumor Metabolism and Immune Microenvironment.
Liu Y, Yan D, Liu F … +6 more , Tang S, Hu X, Jiang Q, Li J, Yi P, Deng D
Curr Med Chem · 2026 Jun · PMID 42381130 · Publisher ↗
INTRODUCTION: Tumor metabolism-related genes participate in tumor metabolic reprogramming and reshape the tumor microenvironment (TME), thereby influencing tumor progression and patient prognosis. However, studies invest...
INTRODUCTION: Tumor metabolism-related genes participate in tumor metabolic reprogramming and reshape the tumor microenvironment (TME), thereby influencing tumor progression and patient prognosis. However, studies investigating pancreatic cancer (PC) are limited. This study examines how aromatic amino acid metabolism and its key genes influence the TME and prognosis in PC. METHOD: We performed an integrated multi-omics analysis of aromatic amino acid metabolism-related genes in various cancers. Patients in the PC cohort were classified into two subtypes with significant metabolic heterogeneity. Analysis of survival outcomes, metabolic pathway activity, tumor microenvironment characteristics, and drug sensitivity in patients with the two subtypes. Key driver genes in aromatic amino acid metabolism were identified and validated in a separate cohort of 150 resected PC patients using immunohistochemistry, with assessments of gene expression, immune cell infiltration, fibroblast markers, and immune checkpoint levels. RESULTS: Genes related to aromatic amino acid metabolism show unique changes and prognostic significance in various s cancers. Lower metabolism of these amino acids is linked to better clinical outcomes. In an independent validation cohort, the expression of phenylalanine hydroxylase (PAH) is associated with overall survival (OS) (p<0.05) and disease-free survival (DFS) (p<0.05) in patients with PC. Both univariate analysis (HR 2.017; p = 0.001) and multivariate analysis (HR 1.653; p = 0.028) corroborate its role as an independent prognostic factor. PAH expression correlated positively with CD8+ TILs (p=0.002) and negatively with FAP (p<0.05) in CAFs. DISCUSSIONS: This study identifies PAH as a critical suppressor of pancreatic cancer progression, potentially by remodeling the tumor immune microenvironment through the enhancement of CD8+ T-cell infiltration and the suppression of FAP+ cancer-associated fibroblasts. Although these findings highlight the prognostic and therapeutic potential of PAH, further mechanistic studies and preclinical validation are necessary to translate these insights into clinical applications. CONCLUSION: This study is the first to reveal PAH as a metabolic immunomodulator and an independent prognostic factor in postoperative PC patients. PAH may affect prostate cancer outcomes by altering the tumor microenvironment.
Pharmacological Targeting of NRF2 Represents a Promising Therapeutic Approach for Pyroptosis-Related Non-Alcoholic Fatty Liver Disease.
Zhang Y, Liu P, Guo Y … +5 more , Hu K, Li X, Liu R, Zhao Y, Wang G
Curr Med Chem · 2026 Jun · PMID 42381129 · Publisher ↗
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by the accumulation of fat within hepatocytes in the absence of excessive alcohol consumption or other identifiable causes of liv...
Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by the accumulation of fat within hepatocytes in the absence of excessive alcohol consumption or other identifiable causes of liver injury. As a disease involving complex pathogenic mechanisms, NAFLD has become the most prevalent chronic liver disease and may progress to more severe conditions. Pyroptosis is a pro-inflammatory form of programmed cell death that is distinct from classical apoptosis. Accumulating evidence suggests that pyroptosis plays a role in the pathogenesis of NAFLD, contributing to disease progression from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Excessive activation of pyroptosis can exacerbate inflammatory responses, induce cellular damage, disrupt immune homeostasis, and impair liver function. Therefore, elucidating the mechanisms and roles of pyroptosis in NAFLD is crucial for the development of effective therapeutic strategies. As a key transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2) has emerged as a promising therapeutic target. Pharmacological modulation of NRF2 has shown potential in treating diseases characterized by oxidative stress and inflammation. Findings from in vitro and animal studies suggest that various compounds that target NRF2 to modulate pyroptosis exhibit notable effects on the initiation and progression of NAFLD. Although most of these agents are still in the early stages of preclinical research, they hold substantial promise for future clinical translation. This review outlines recent advances in pyroptosis-related research in NAFLD and highlights pharmacological targeting of NRF2 as a promising therapeutic approach for pyroptosis-mediated NAFLD.
Unlocking the Prognostic Power of the m-CALLY Index in Cardiovascular-Kidney-Metabolic Syndrome.
Sun J, Du G, Xu D … +9 more , Wang F, Yu Y, Wang J, Yan Z, Sufianov A, Beylerli O, Gareev I, Wang C, Che S
Curr Med Chem · 2026 Jun · PMID 42367126 · Publisher ↗
INTRODUCTION: Cardiovascular-Kidney-Metabolic (CKM) syndrome is a multi- -system disorder driven by chronic inflammation and immune-nutritional imbalances. This study aimed to evaluate the prognostic value of the modifie...
INTRODUCTION: Cardiovascular-Kidney-Metabolic (CKM) syndrome is a multi- -system disorder driven by chronic inflammation and immune-nutritional imbalances. This study aimed to evaluate the prognostic value of the modified C-reactive protein-- to-albumin-to-lymphocyte (m-CALLY) index within the integrative CKM framework. METHODS: Data from 9,135 adults with CKM syndrome (weighted population: 76,768,947) were extracted from NHANES (2001-2010). Participants were stratified into Stages 0-4 based on the 2023 AHA scientific statement. The m-CALLY index was calculated and log-transformed, with mortality assessed via National Death Index linkage. Predictive performance was compared against the Prognostic Nutritional Index (PNI) using log-likelihood ratio tests. RESULTS: During follow-up, 1,881 all-cause and 494 cardiovascular deaths were identified. Multivariable Cox analysis demonstrated that the m-CALLY index was inversely associated with mortality risk. After full adjustment, each 1-SD increase in m-CALLY was associated with a 13% lower risk of all-cause mortality (HR: 0.87, 95% CI: 0.83-0.90). Compared to the lowest quartile (Q1), the highest quartile (Q4) exhibited a 39% reduction in all-cause mortality (HR: 0.61, 95% CI: 0.49-0.75) and a 17% reduction in cardiovascular mortality (HR: 0.83, 95% CI: 0.76-0.90). Notably, m-CALLY demonstrated superior predictive accuracy over the PNI index (log-likelihood: -4288.45 vs. -4333.92). These associations remained consistent across all CKM stages (P-interaction > 0.05). DISCUSSION: The study's findings suggest that integrating inflammation, nutrition, and immunity via the m-CALLY index offers a more comprehensive assessment of the CKM pathophysiological burden than traditional indices. As a routine laboratory-based tool, it provides a cost-effective strategy for risk stratification across the entire CKM spectrum. CONCLUSION: Elevated m-CALLY levels are independently associated with significantly reduced risks of all-cause and cardiovascular mortality in the CKM population. This index may facilitate integrated risk stratification and personalized management in clinical practice.
Ferritinophagy-Related Genes in Breast Cancer: Insights from Multi-Omics Analysis.
Luo W, Xu P, Wu H … +2 more , Ma X, Kang H
Curr Med Chem · 2026 Jun · PMID 42367125 · Publisher ↗
INTRODUCTION: Breast cancer (BRCA) remains a major health burden. Ferritinophagy, a selective form of autophagy regulating iron homeostasis, has been linked to tumor progression. This study aims to explore ferritinophagy...
INTRODUCTION: Breast cancer (BRCA) remains a major health burden. Ferritinophagy, a selective form of autophagy regulating iron homeostasis, has been linked to tumor progression. This study aims to explore ferritinophagy-associated biomarkers and develop a prognostic model in BRCA through integrative multi-omics analysis. METHODS: 30 differentially expressed ferritinophagy-related differentially expressed genes (FeRDEGs) were detected in BRCA, followed by functional enrichment analyses to investigate their biological significance. The prognostic risk model was formulated by integrating Cox and LASSO regression analyses. Patients were stratified based on calculated risk scores, and model performance was validated in an independent cohort. Additionally, we assessed mutation profiles, drug-gene interactions, and immune infiltration characteristics. RESULTS: Functional annotation and clustering revealed links to cellular stress responses, autophagy regulation, and metabolic remodeling. Through univariate Cox and LASSO regression analyses, ATG5, JUN, and TFRC were identified as significantly associated with patient survival. A multigene prognostic model was constructed based on their expression, which facilitated risk stratification of patients with statistically significant differences in survival outcomes. The two risk groups also exhibited different mutational landscapes, druggable gene profiles, and drug sensitivity, suggesting implications for personalized therapy. Immune infiltration analysis offered additional contextual support for the findings. DISCUSSION: The multi-gene prognostic model based on ATG5, JUN, and TFRC demonstrated stable risk stratification and potential clinical utility in breast cancer. Future validation with larger, multi-center cohorts and additional multi-omics features could further enhance its predictive performance. CONCLUSION: We explored the biological relevance of FeRDEGs and established a prognostic model based on ATG5, JUN, and TFRC. The model was validated across multiple dimensions, supporting its potential value in risk stratification and clinical application. These findings might contribute to offering a foundation for exploring therapeutic strategies targeting iron metabolism and autophagy-related pathways.
Research Progress on Natural Products and Synergistic Nanostrategies for Targeting Ferroptosis in Osteosarcoma.
Chen C, Zuo Q, He Q … +5 more , Yangyang Z, Wu G, Luo H, Li X, Zhang F
Curr Med Chem · 2026 Jun · PMID 42367124 · Publisher ↗
Emerging evidence suggests that ferroptosis, a unique iron-dependent form of regulated cell death driven by lipid peroxidation and morphologically distinct from apoptosis or necrosis, plays a vital role in the pathophysi...
Emerging evidence suggests that ferroptosis, a unique iron-dependent form of regulated cell death driven by lipid peroxidation and morphologically distinct from apoptosis or necrosis, plays a vital role in the pathophysiological progression and therapy resistance of osteosarcoma (OS). Accumulating evidence supports ferroptosis induction as a critical therapeutic strategy for OS, and pharmacological activation of ferroptosis by natural products represents a promising target for combating this malignancy. In this review, the core mechanisms of ferroptosis (including dysregulated iron/lipid/amino acid metabolism and autophagy-mediated regulation) and their roles in OS pathogenesis and chemoresistance are systematically described. Finally, emerging findings in treating OS through pharmacological induction of ferroptosis by bioactive natural compounds (e.g., flavonoids, curcuminoids, and terpenoids), functional nanomaterials (e.g., targeted drugloaded nanoparticles and GSH-depleting agents), and engineered exosomes are comprehensively summarized. Collectively, available evidence-predominantly from cell-line and xenograft studies-suggests that ferroptosis induction by natural products and nano/exosome-enabled delivery platforms can suppress OS growth and sensitize tumors to standard chemotherapeutics in preclinical models, including selected drug-resistant settings. However, clinical translation will require rigorous PK/PD and biodistribution characterization, definition of a therapeutic index and off-tumor ferroptosis liabilities, validation in orthotopic/bone-microenvironment models, and biomarker-guided stratification to identify responsive OS subsets.
Revealing Antihypertensive Drugs for Reducing NAFLD Risk: Genetic Evidence from a Mendelian Randomization Study.
Zhang K, Guo L, Gan Y … +7 more , Chen Y, Jiang Z, Yu S, Lei Q, Ran L, Zheng J, Hu G
Curr Med Chem · 2026 Jun · PMID 42367123 · Publisher ↗
BACKGROUND: Longstanding observational work has associated Nonalcoholic Fatty Liver Disease (NAFLD) with hypertension and suggested that antihypertensive therapy may slow NAFLD progression. However, confounding and rever...
BACKGROUND: Longstanding observational work has associated Nonalcoholic Fatty Liver Disease (NAFLD) with hypertension and suggested that antihypertensive therapy may slow NAFLD progression. However, confounding and reverse causation in these studies obscure the effects on the risk for NAFLD. To tackle this problem, the study utilized Mendelian randomization (MR) to test the causal antihypertensive effects of drug targets on NAFLD and to evaluate safety. MATERIALS AND METHODS: A total of 37 antihypertensive drug targets from genome-wide association studies (GWAS) were used to instrument Single-Nucleotide Polymorphisms (SNPs) and perform MR to estimate causal relationships with NAFLD risk and possible adverse outcomes. The study examined robustness through heterogeneity tests, assessments of horizontal pleiotropy, leave-one-out analyses, and meta-analysis. Meanwhile, the study profiled possible side effects of prioritised targets with phenome-wide association studies (PheWAS). RESULTS: Genetic proxies for beta-1 adrenergic receptor (ADRB1) antagonists, solute carrier family 12 member 1 (SLC12A1) inhibitors, and neuraminidase 1 (NEU1) inhibitors were associated with reduced NAFLD risk in three distinct analyses, according to MR and meta-analysis data. Combining MR and PheWAS results indicates that the known classes, ADRB1 antagonists and SLC12A1 inhibitors, may be safer. DISCUSSION: Compared with previous studies, this study provided a more comprehensive genetic analysis of existing antihypertensive drug targets, suggesting that inhibition of ADRB1, SLC12A1, and NEU1 can significantly reduce the risk of NAFLD while assessing their safety. Based on the results of this study, future clinical translation must carefully balance the benefits and risks and achieve precise intervention through an individualized medication strategy. CONCLUSION: This study, according to current knowledge, offers the first genetic evidence that antihypertensive drugs can lower NAFLD risk. ADRB1 and SLC12A1 appear to be promising therapeutic targets for NAFLD, whereas NEU1 inhibition warrants a more cautious appraisal to balance efficacy with safety.
Identification of Diagnostic Biomarkers Related to Oxidative Stress in Rheumatoid Arthritis.
Tang H, Ji W, Liu Y … +6 more , Meng Y, Lv D, Gao J, Ma L, Guo Y, Zhao Y
Curr Med Chem · 2026 Jun · PMID 42367122 · Publisher ↗
BACKGROUND: This study aimed to identify oxidative stress-related genes as potential diagnostic biomarkers for rheumatoid arthritis (RA). METHODS: We first obtained RA transcriptomic data from the Gene Expression Omnibus...
BACKGROUND: This study aimed to identify oxidative stress-related genes as potential diagnostic biomarkers for rheumatoid arthritis (RA). METHODS: We first obtained RA transcriptomic data from the Gene Expression Omnibus (GEO) database and calculated oxidative stress scores using single-sample gene set enrichment analysis (ssGSEA). Differentially expressed genes (DEGs) were identified by limma (R). Gene Ontology (GO) enrichment was performed using the clusterProfiler package, and weighted gene co-expression network analysis (WGCNA) was used to classify oxidative stress modules. Candidate biomarker genes for RA were screened by support vector machine-recursive feature elimination (SVM-RFE), least absolute shrinkage and selection operator (LASSO), random forest, and eXtreme Gradient Boosting (XGBoost). We then constructed a logistic regression-based diagnostic model. Immune infiltration analysis, pathway enrichment analysis, single-cell RNA sequencing, and in vitro experiments were employed to comprehensively elucidate the expression profiles and potential mechanisms of action of the identified genes in rheumatoid arthritis (RA). RESULTS: RA samples had higher oxidative stress scores than normal samples. WGCNA showed that the cyan module was linked to oxidative stress, from which 88 potential genes were screened. Five signature genes (CARS2, VCP, FCGR2A, ITGB2, SETD2) were selected. RT-qPCR showed higher expression of the five genes in MH7A than in HFLS cells. The logistic model developed based on these genes demonstrated robust performance, with an area under the curve (AUC) greater than 0.9 in both training and validation sets. The model was positively associated with ImmuneScore and the infiltration of specific immune cells. Notably, the model genes showed distinct expression patterns in plasmacytoid dendritic cells (pDCs) and monocytes. DISCUSSION: The five oxidative stress-related genes identified in this study exhibited elevated expression in RA. Immune infiltration and pathway enrichment analysis revealed their potential contribution to immune dysregulation via IL6-JAK-STAT3, ROS, and hypoxia pathways in RA. CONCLUSION: This study established a five-oxidative-stress-gene diagnostic model, offering a potential molecular tool for early RA detection and immune-based patient stratification.
Mechanistic Insights into Ginkgo Biloba Extract's Anti-Inflammatory Effects in COPD: Regulation of Th1/Th2 Balance via the p38 MAPK Pathway.
Zhang P, Liao L, Dong X … +4 more , Peng Z, Huang S, Guo D, Sun H
Curr Med Chem · 2026 Jun · PMID 42337888 · Publisher ↗
OBJECTIVE: To investigate the anti-inflammatory and therapeutic effects of Ginkgo biloba extract (GBE) on chronic obstructive pulmonary disease (COPD), and to elucidate the underlying molecular mechanism by which GBE mod...
OBJECTIVE: To investigate the anti-inflammatory and therapeutic effects of Ginkgo biloba extract (GBE) on chronic obstructive pulmonary disease (COPD), and to elucidate the underlying molecular mechanism by which GBE modulates the p38 mitogen-activated protein kinase (MAPK) signaling pathway and maintains the balance of T helper 1 (Th1)/T helper 2 (Th2) cells, thereby alleviating pulmonary inflammation, alveolar destruction and airway remodeling in COPD. METHODS: Rats were randomly assigned to one of six groups: a blank group, a COPD model group, a high-dose GBE group (14 mg/kg/day), a medium-dose GBE group (7 mg/kg/day), a low-- dose GBE group (3.5 mg/kg/day), and a p38 MAPK inhibitor group, with 15 rats in each group. Except for the blank group, COPD models were established in the other groups using cigarette smoke (CS) inhalation combined with intratracheal lipopolysaccharide (LPS) instillation. Following the establishment of the models, the respective treatments were administered to each group. After the drug interventions, histological examination using HE staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, quantitative real-time polymerase chain reaction (PCR), and Western blot analysis were performed to explore the underlying mechanisms. RESULTS: Different doses of GBE and the p38 MAPK inhibitor alleviated alveolar destruction and airway remodeling in COPD rats, reducing inflammatory infiltration around alveoli and bronchi. Compared with the COPD model group, all GBE dose groups and the p38 MAPK inhibitor group inhibited p38 MAPK signaling and the activation of upstream regulatory factors (TLR3, MKK3, MKK6) (p<0.05), reduced CD4+ T cell differentiation toward Th1 (p<0.05), suppressed secretion of inflammatory cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2) (p<0.05), and mitigated immune-inflammatory damage to alveoli and bronchi. DISCUSSION: The core pathological issues of COPD include immune-inflammatory imbalance, destruction of alveolar structure, and airway remodeling. This study indicates that GBE can act simultaneously on these three core aspects. This research links GBE with the p38 MAPK signaling pathway and the regulation of Th1/Th2 balance. It improves airway remodeling by regulating the p38 MAPK pathway and corrects immune-inflammatory disorders by maintaining the Th1/Th2 balance, providing clear molecular mechanism support for the action of GBE, rather than merely remaining at the level of phenomenon observation. CONCLUSION: GBE alleviates COPD immune-inflammatory responses, prevents alveolar destruction, and attenuates airway remodeling by regulating the p38 MAPK signaling pathway to maintain Th1/Th2 balance, thereby exerting therapeutic effects on COPD.
Inflammatory Cytokines May Mediate the Causal Relationship between Metabolites and Primary Sclerosing Cholangitis: A Bidirectional Mediation Mendelian Randomization Study.
Liu H, Zhong Z, Ning S
Curr Med Chem · 2026 Jun · PMID 42337887 · Publisher ↗
INTRODUCTION: The causal links between metabolites, inflammatory cytokines, and Primary Sclerosing Cholangitis (PSC) remain elusive. This study used Mendelian Randomization (MR) to elucidate these mechanistic pathways. M...
INTRODUCTION: The causal links between metabolites, inflammatory cytokines, and Primary Sclerosing Cholangitis (PSC) remain elusive. This study used Mendelian Randomization (MR) to elucidate these mechanistic pathways. METHODS: Genome-Wide Association Study (GWAS) summary statistics for 1,400 metabolites (n = 8,299), 91 inflammatory plasma proteins (n = 14,824), and PSC (2,871 cases and 12,019 controls) were leveraged. Bidirectional MR evaluated potential causal directionality, and mediation analysis examined the intermediary roles of cytokines. Sensitivity analyses ensured the robustness of the findings. RESULTS: The findings revealed that 52 metabolites are associated with PSC, with 18 identified as risk factors and 34 as protective factors. Four inflammatory proteins were implicated, with IL-10RB acting as a protective mediator, while NKR2B4, CXCL9, and TNFSF12 served as risk factors. Mediation analysis revealed that these cytokines partially mediated the associations between eight metabolites and disease susceptibility, indicating a complex regulatory network involving metabolic and immune pathways. DISCUSSION: This study provides suggestive evidence for links among metabolites, inflammatory cytokines, and PSC. Mediation MR analysis revealed that four inflammatory cytokines, IL-10RB, CXCL9, TNFSF12, and NKR2B4, partially mediate the effects of specific metabolites on PSC risk. This finding suggests that metabolites may indirectly influence disease progression by modulating distinct inflammatory pathways. CONCLUSION: This study delineates a preliminary metabolic-immune interactome in PSC from a genetic standpoint, offering novel insights into the disease's complex pathogenesis. The prioritized cohorts of metabolites and cytokines identified herein represent prime candidates for the future development of novel biomarkers and the design of targeted therapeutic interventions.
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