Molecular And Cellular Biochemistry[JOURNAL]
Sun
200 papers
The pivotal role of mitochondria in the pathogenesis and treatment of liver failure: a comprehensive review.
Peng Q, Hao L, Li S … +7 more , Yu F, Li N, Luo X, Yue J, Luo Q, Zheng K, Hu X
Mol Cell Biochem · 2026 May · PMID 41689714 · Publisher ↗
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by high mortality rates. A growing body of evidence highlights mitochondrial dysregulation as a central pathogenic driver in these dis...
Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are characterized by high mortality rates. A growing body of evidence highlights mitochondrial dysregulation as a central pathogenic driver in these diseases. We provide a detailed examination of mitochondrial structure and core physiological functions in hepatic homeostasis, including mitochondrial DNA (mtDNA) replication, adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) homeostasis, cell apoptosis, calcium homeostasis, mitophagy and mitochondrial biogenesis. We further elaborate on the key mechanisms underlying mitochondrial dysfunction in liver failure, including mitochondrial structural dysfunction, mtDNA damage, energy metabolism disruption, oxidative stress imbalance, inflammatory response dysregulation, cell apoptosis dysregulation, calcium homeostasis imbalance and autophagy dysregulation. These pathological processes are triggered or exacerbated by multiple factors, including genetic defects, drugs/toxins, and viral/bacterial infections. Recognizing the pivotal role of mitochondria, we summarize promising therapeutic interventions that have emerged, encompassing mitochondrial protection, mitochondrial restoration and mitochondrial replacement. Finally, we outline critical unresolved gaps in the field, such as the determinants of hepatocyte mitochondrial selective vulnerability, validated mitochondrial-specific biomarkers, and synergistic interactions between causative factors. Collectively, this review summarizes the multifaceted role of mitochondrial dysfunction in ALF/ACLF and highlights targeted strategies to interrupt the pathogenic cascade, offering potential avenues to improve patient outcomes.
MALAT1 promotes acetaminophen-induced hepatocyte pyroptosis by stabilizing Rac1 through its interaction with MTDH and the hepatoprotective role of muniziqi saifula.
Kuerban Y, Gul A, Wusiman Z … +8 more , Huo S, Ruermaiti M, Wahefu A, Wushouer S, Kamili M, Aierken A, Li Z, Talifu A
Mol Cell Biochem · 2026 Apr · PMID 41689713 · Publisher ↗
Acetaminophen (APAP)-induced acute liver injury (ALI) is a leading cause of acute liver failure, in which pyroptosis plays an important pathogenic role; however, the involvement of the long non-coding RNA MALAT1 remains...
Acetaminophen (APAP)-induced acute liver injury (ALI) is a leading cause of acute liver failure, in which pyroptosis plays an important pathogenic role; however, the involvement of the long non-coding RNA MALAT1 remains unclear. Here, we investigated the role of MALAT1 in APAP-induced hepatocyte pyroptosis using THLE-2 cells and an ALI mouse model. MALAT1 expression was markedly upregulated following APAP exposure, whereas MALAT1 knockdown significantly reduced the expression of pyroptosis-related proteins (NLRP3, cleaved Caspase1, and GSDMD-N), decreased IL-1β and IL-18 release, and attenuated pyroptotic cell death. Mechanistically, MALAT1 directly interacted with metadherin (MTDH), thereby stabilizing Rac1 mRNA and enhancing Rac1 expression; overexpression of MTDH or Rac1 partially reversed the anti-pyroptotic effects of MALAT1 silencing. Importantly, Muniziqi Saifula (SFL) treatment suppressed the MALAT1/MTDH/Rac1 axis and alleviated APAP-induced hepatocyte pyroptosis both in vitro and in vivo. Collectively, these findings identify a MALAT1–MTDH–Rac1 signaling axis that promotes APAP-induced hepatocyte pyroptosis and suggest that SFL exerts hepatoprotective effects by targeting this pathway, providing potential therapeutic insight for drug-induced liver injury.
The role and mechanism of histone deacetylase in COPD.
Tang H, Gao Q, Xie S
Mol Cell Biochem · 2026 Apr · PMID 41689712 · Publisher ↗
Chronic obstructive pulmonary disease (COPD) is a major global health challenge characterized by persistent airflow limitation. Persistent chronic inflammation serves as the primary driver of its pathogenesis, leading to...
Chronic obstructive pulmonary disease (COPD) is a major global health challenge characterized by persistent airflow limitation. Persistent chronic inflammation serves as the primary driver of its pathogenesis, leading to key structural and functional impairments, including airway remodeling, emphysema, and skeletal muscle dysfunction. Histone deacetylases (HDACs), a class of enzymes crucial for epigenetic regulation, play a pivotal role in the progression of COPD. This review provides a systematic overview of the structural and functional characteristics of HDACs and explores their involvement in the multifaceted pathology of the disease. Given their potential as therapeutic targets, a comprehensive understanding of HDAC-mediated mechanisms may provide a rationale for developing novel HDAC inhibitors and advancing treatment strategies for COPD.
Liver-specific SLC13A3 modulation alleviates MASLD by regulating NAD metabolism.
Du J, Shen M, Mu Y … +7 more , Peng S, Xu Z, Yang X, Yang B, Luo P, Yan H, He Q
Mol Cell Biochem · 2026 Apr · PMID 41689711 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic optio...
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1, CD36, PPARγ, and SCD1. These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.
Gomisin A and metformin co-treatment attenuates diabetic nephropathy and cardiovascular dysfunction by modulating the AGE/RAGE pathway in a diabetic rat model.
Nayak SPRR, Pohokar P, Arasu MV … +2 more , Soundharrajan L, Arockiaraj J
Mol Cell Biochem · 2026 Apr · PMID 41689710 · Publisher ↗
Diabetic nephropathy (DN) is a severe complication of type 2 diabetes mellitus (T2DM) that is frequently accompanied by cardiovascular disease (CVD) and chronic kidney disease (CKD). The current therapeutic options for D...
Diabetic nephropathy (DN) is a severe complication of type 2 diabetes mellitus (T2DM) that is frequently accompanied by cardiovascular disease (CVD) and chronic kidney disease (CKD). The current therapeutic options for DN and CVD are limited and often produce significant adverse effects. In this study, we evaluated the renal and cardioprotective effects of natural Gomisin A, alone and in combination with metformin, in a diabetic model. While treatment with Gomisin A at 20 mg/kg slightly improved glycemic control and renal function, co-administration with metformin yielded better results. The combined treatment significantly lowered blood glucose levels and improved β-cell integrity. It also prevented renal hypertrophy and reduced inflammation, as evidenced by decreased serum creatinine, urea, phosphorus, lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels. Additionally, the combination modulated the AGE/RAGE pathway, thereby downregulating NF-κB expression, reducing proinflammatory cytokines, and lowering TGF-β expression in renal tissues. Cardiac protective effects were also observed, including inhibition of myocardial thickening and hypertrophy. These findings suggest that Gomisin A and metformin work synergistically to mitigate the progression of DN and CVD, supporting the potential of Gomisin A as a nutraceutical adjunct to conventional anti-diabetic treatments.
MiRNA based liquid biopsy for castration-resistant prostate cancer diagnostics.
Konoshenko MY, Saitkulova MM, Shutko EV … +3 more , Ostaltsev IA, Laktionov PP, Bryzgunova OE
Mol Cell Biochem · 2026 Apr · PMID 41689709 · Publisher ↗
Androgen deprivation therapy (ADT) is widely used for prostate cancer (PCa) treatment. However, this treatment is not curative, and PCa progresses despite ADT, becoming castration-resistant (CR). Castration-resistant pro...
Androgen deprivation therapy (ADT) is widely used for prostate cancer (PCa) treatment. However, this treatment is not curative, and PCa progresses despite ADT, becoming castration-resistant (CR). Castration-resistant prostate cancer (CRPCa) is a highly aggressive form of PCa that progresses, metastasizes, and develops treatment resistance rapidly. MiRNAs are known to be involved in cancer development mechanisms, including cell cycle regulation, apoptosis, angiogenesis, and epithelial-mesenchymal transition. The aim of the present work was a comparative analysis of the expression of 14 miRNAs involved in PCa development in hormone-sensitive prostate cancer (HSPCa) patients before any treatment, after ADT, in CRPCa, as well as in healthy donors (HD), to assess their diagnostic potential for CR. 44 differentially expressed miRNA ratios were found in urine extracellular vesicles (EVs), 41 in cell-free urine, and 35 in plasma EVs. ROC curve analysis was performed using three different control groups: HD + HSPCa, HSPCa, and HSPCa under maximal androgen blockade (MAB) treatment. For each biofluid and control group, the most diagnostically effective miRNA ratios were evaluated to identify minimal and redundant diagnostic panels. Urine EVs provided the most diagnostically efficient miRNA ratios and panels. For the HD + HSPCa control group, the minimal panel consisting of 3 miRNA ratios was able to diagnose 95% of CRPCa patients, while a partially redundant panel of 5 miRNA ratios diagnosed 90% of CRPCa patients at least twice. For the HSPCa control group, two minimal panels consisting of 2 miRNA ratios each were able to diagnose 100% of CRPCa patients, and a redundant panel of 6 different miRNA ratios also diagnosed 100% of CRPCa patients at least twice. For the MAB control group, a minimal panel of 3 miRNA ratios diagnosed 100% of CRPCa patients, and a partially redundant panel consisting of 4 different miRNA ratios diagnosed 95% of CRPCa patients.
Correction to: Hypoxia-induced histone lactylation promotes pulmonary arterial smooth muscle cells proliferation in pulmonary hypertension.
Chen A, Chen Z, Huang B … +3 more , Lian G, Luo L, Xie L
Mol Cell Biochem · 2026 Apr · PMID 41642471 · Full text
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Unraveling the impact of chemoradiotherapy on hematopoietic function in cancer patients: a metabolomics-driven mechanistic investigation.
Yang G, Chen S, Wei M
Mol Cell Biochem · 2026 Apr · PMID 41642470 · Publisher ↗
Myelosuppression, a dose-limiting toxicity affecting a substantial proportion of chemotherapy patients globally (Wilson et al in Lancet Oncol 20(6):769-780, 2019. https://doi.org/10.1016/S1470-20451930163-9) remains a ma...
Myelosuppression, a dose-limiting toxicity affecting a substantial proportion of chemotherapy patients globally (Wilson et al in Lancet Oncol 20(6):769-780, 2019. https://doi.org/10.1016/S1470-20451930163-9) remains a major clinical barrier to curative intent therapies and long-term survival. It leads to treatment delays, dose reductions, infection-related morbidity, and mortality, thereby imposing substantial healthcare burdens and diminishing patient quality of life. Here, we integrate recent metabolomics-driven discoveries to characterize chemotherapy- and radiotherapy-induced metabolic dysregulation across glucose, amino acid, lipid, and mitochondrial pathways and delineate how these alterations impair hematopoietic stem cell (HSC) function and disrupt the bone marrow microenvironment. We further connect metabolic perturbations with functional consequences, including HSC quiescence loss, oxidative stress, stromal niche remodeling, and immune dysregulation. We highlight emerging metabolite-based biomarkers, metabolic checkpoints, and nutrient-targeted therapeutic strategies capable of preventing or mitigating myelosuppression. In addition, we discuss metabolic-pathway-specific interventions, such as amino acid deprivation therapy, ketone-mediated hematopoietic protection, and mitochondrial stress modulation, emphasizing the translational potential of precision metabolic monitoring. Our analysis underscores the central role of precision metabolomics in predicting, stratifying, and reducing treatment-related hematotoxicity, providing a mechanistic and clinically actionable framework for improving therapeutic tolerance. This metabolomics-centered perspective supports individualized intervention strategies that may ultimately enhance therapeutic index and reduce hematological complications.
Mesenchymal stem cell exosomes alleviate ischemic myocardial injury by miR-125b-5p/BTG2 pathway.
Luo L, Li L, Wu S … +2 more , Zeng X, Fan L
Mol Cell Biochem · 2026 Apr · PMID 41642469 · Publisher ↗
MicroRNAs mediate the protective effects of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) against myocardial injury. This study aimed to elucidate the specific role of exosomal miR-125b-5p in ischemic my...
MicroRNAs mediate the protective effects of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) against myocardial injury. This study aimed to elucidate the specific role of exosomal miR-125b-5p in ischemic myocardial injury, focusing on its regulatory interaction with B-cell translocation gene 2 (BTG2). Murine BMSCs were transfected with miR-125b-5p inhibitor or negative-control (NC) oligonucleotides and then used to generate miR-125b-5p-knockdown (miR-125b-5p)-Exos or NC-Exos under hypoxic condition. In vivo, myocardial infarction (MI) was induced by LAD ligation, followed by intramyocardial injection with 50 μl of PBS, or containing 200 μg of NC-Exos, or miR-125b-5p-Exos. In vitro, HL-1 cells were treated with NC-Exos or miR-125b-5p-Exos at a final concentration of 50 μg/ml under hypoxia/serum-deprived (HSD) condition. Cell apoptosis, inflammation, fibrosis, cardiac function and BTG2 expression were assessed. Exosomes uptake was detected by fluorescence microscopy after exosomes labeled with DiD dye were injected into ischemic myocardium or co-cultured with HL-1 cells under HSD condition. Dual-luciferase reporter assay was applied to validate miR-125b-5p/BTG2 interaction. When compared with group MI, treatment with NC-Exos significantly alleviated the inflammatory response (inflammation score: 1.70 ± 0.37 vs. 3.47 ± 0.22, P < 0.01), inhibited cardiac fibrosis (fibrotic area ratio: 15.98% ± 2.79% vs. 31.55% ± 3.54%, P < 0.01), and improved cardiac function (ejection fraction: 49.48% ± 6.43% vs. 29.35% ± 5.79%, P < 0.01 and fractional shortening: 30.88% ± 3.70% vs. 16.15 ± 2.72%, P < 0.01). NC-Exos reduced the cell apoptosis by 41.5% in vivo (18.00% ± 3.74% vs. 30.75% ± 3.86%, P < 0.01) when compared with group MI and by 52.2% in vitro (10.48% ± 1.80% vs. 21.93% ± 1.76%, P < 0.001) when compared with group HSD. Treatment with NC-Exos also resulted in remarkable down-regulation of BTG2 expression. The knockdown of miR-125b-5p weakened these protective effects of NC-Exos. The effective uptake of DiD-labeled exosomes by ischemic myocardium and HL-1 cells were confirmed by fluorescence microscopy. Dual-luciferase reporter assay further confirmed that BTG2 is the target of miR-125b-5p. BMSC-derived exosomes confer cardioprotection, at least in part, by transferring miR-125b-5p into cardiomyocytes to target BTG2.
TMEM158-mediated TGF-β signaling pathway modulates the sensitivity of TP53-deficient osteosarcoma to USP14 inhibitors.
Chen ZY, Yasen M, Jiang SY … +11 more , Ye ZY, Yang QX, Lu CN, Shi Y, Liu XY, Du TT, Tang XM, Fu D, Ma YS, Yu H, Wang XF
Mol Cell Biochem · 2026 Apr · PMID 41642468 · Publisher ↗
Previous studies have demonstrated that the USP14 inhibitor IU1 and USP14/UCHL5 inhibitor b-AP15 can extend the survival period of TP53-deficient mice with spontaneous osteosarcoma (OS). However, the underlying molecular...
Previous studies have demonstrated that the USP14 inhibitor IU1 and USP14/UCHL5 inhibitor b-AP15 can extend the survival period of TP53-deficient mice with spontaneous osteosarcoma (OS). However, the underlying molecular mechanisms remain to be fully elucidated. The transmembrane protein TMEM158 has been identified as a key regulator in the progression of various cancers. Nevertheless, its functional role in OS remains largely unknown. In this study, we conducted comprehensive bioinformatics analyses-including cluster analysis, differential expression analysis, and functional enrichment analysis-on clinical OS databases to assess the correlation between TMEM158 expression and the proteasome-associated USP14 and UCHL5. Primary tumor cells (TP53-deficient OS cells), SAOS-2 and U-2OS cells were treated with IU1 or b-AP15, respectively. The expression levels of TMEM158 were quantified using qPCR. Subsequently, TMEM158 was knocked down in three cell lines, and subsequent changes in cellular activity and TGF-β signaling were evaluated. Concurrently, single-cell RNA sequencing data were analyzed to identify cell types exhibiting high TMEM158 expression and to explore their associated intercellular communication patterns. Both IU1 and b-AP15 significantly prolonged the survival of TP53-deficient OS mice and exhibited enhanced cytotoxic effects on TP53-deficient OS cells. These compounds selectively suppressed TMEM158 expression in TP53-deficient primary OS and SAOS-2 cells. Bioinformatics analysis revealed that TMEM158 is positively correlated with USP14 and UCHL5 expression and serves as an independent prognostic marker for poor clinical outcomes in OS patients. Experimental validation showed that TMEM158 knockdown significantly reduced the viability of TP53-deficient primary OS and SAOS-2 cells, and inhibited TGF-β pathway activation. Osteoblastic OS cells displayed concurrent suppression of the P53 pathway and activation of the TGF-β pathway, with a strong covariant relationship between TMEM158 and activity of TGF-β pathway. Meanwhile, there may be intercellular TGF-β signaling communication between osteoblastic OS cells with high expression levels of TMEM158 and macrophages. Our findings demonstrated that the TMEM158-TGF-β pathway plays a central role in mediating the heightened sensitivity of TP53-deficient OS to USP14 inhibition. Targeting this pathway may represent a promising therapeutic strategy for precision treatment of osteosarcoma.
HMGA2 promotes hepatocellular carcinoma progression by regulating tumor-associated macrophage via Notch1/CCL2 signaling.
Xing Z, Xun J, Deng L
Mol Cell Biochem · 2026 Apr · PMID 41632427 · Publisher ↗
Tumor-associated macrophages (TAMs) primarily exhibit a protumor M2-like phenotype, which substantially affects hepatocellular carcinoma (HCC) progression via their immunosuppressive properties. The oncoprotein high-mobi...
Tumor-associated macrophages (TAMs) primarily exhibit a protumor M2-like phenotype, which substantially affects hepatocellular carcinoma (HCC) progression via their immunosuppressive properties. The oncoprotein high-mobility gene group A2 (HMGA2) is abnormally overexpressed in HCC. However, the mechanisms by which HMGA2 regulates the HCC tumor microenvironment remain incompletely understood. The relative expression levels of HMGA2 in HCC tissues and adjacent peritumoral tissues were determined by quantitative real-time polymerase chain reaction (qRT‒PCR), Western blotting, and immunohistochemistry (IHC). The biological function of HMGA2 was determined by CCK-8 and Transwell migration assays. In vitro coculture assays were used to investigate the role of HMGA2 in the migration and polarization of macrophages in HCC cells. The in vivo tumor xenograft model to investigate the impact of HMGA2 loss-of-function on tumor growth and TAM infiltration. The mRNA and protein expression levels of HMGA2 were increased in HCC tissues and cell lines. Overexpression of HMGA2 increased the proliferation of HCC cells while promoting HCC cell migration. HMGA2 expression was positively correlated with CD68 + and CD163 + expression, and elevated M2 macrophages in HCC patients were significantly associated with poor prognosis. Moreover, we found that HMGA2 in HCC cells facilitated macrophage recruitment and M2 polarization by inducing CCL2 secretion by upregulating NOTCH1, thus promoting macrophage recruitment in vitro. Finally, knockdown of HMGA2 suppressed HCC growth and reduced M2-TAM infiltration in vivo. This research indicated that HMGA2 overexpression in HCC cells promotes the recruitment of macrophages and M2 polarization by mediating CCL2 secretion through Notch1 upregulation, thereby promoting HCC tumor immunosuppression.
Combination gene therapy with AAV based RPE65 and survivin vectors sustains phenotypic rescue in neural retina of LCA2 mice.
Singh V, Huda S, Narendra Kumar G … +1 more , Jayandharan GR
Mol Cell Biochem · 2026 Apr · PMID 41632426 · Publisher ↗
Leber congenital amaurosis type 2 (LCA2) is an inherited retinal disorder, with severe vision impairment in children, progressing to complete blindness in the later stages of life. The current approved treatment involves...
Leber congenital amaurosis type 2 (LCA2) is an inherited retinal disorder, with severe vision impairment in children, progressing to complete blindness in the later stages of life. The current approved treatment involves Adeno-associated virus (AAV) vector serotype 2-based subretinal delivery of human RPE65 gene. However, long-term follow-up have reported gradual loss of phenotypic response. To overcome this, we have pursued strategies aimed at improving the transduction efficacy of the vector, optimizing the transgene for enhanced protein expression and co-delivering the therapeutic vector along with the anti-apoptotic factor, Survivin /baculoviral IAP repeat containing 5 (BIRC5) gene in the neural retina. We tested the efficacy of modified RPE65 transgene (Kozak/ codon optimized [CodOpt]) carried by an improved AAV2 vector (AAV2K665Q) against RPE65 wild type (WT) and observed that vector carrying CodOptRPE65 performed 1.8-fold better in vitro. Subsequently, the codon optimized RPE65 transgene containing vector was evaluated in a pre-clinical mouse model of LCA2 (rd12) with co-delivery of Survivin in an AAV5 vector. Animals were monitored for up to 6 months, and electroretinography revealed improved A- and B-wave response of 2.57- fold and 1.76-fold, respectively in combination treated eyes (CodOptRPE65 + Survivin) as compared to mock group. Co-delivery of CodOptRPE65 + Survivin did not significantly enhance retinal function by ERG when compared to AAV2K665Q-CMV-codon-optimized RPE65 alone. However, immunohistochemistry revealed that expression of apoptotic marker Bax is significantly reduced and anti-apoptotic marker Bcl2 significantly increased in animals receiving the combination therapy. A TUNEL assay further confirmed the decrease in apoptosis in the combination treatment group. These findings suggest that incorporating anti-apoptotic factors may strengthen the phenotypic rescue and control degeneration of the neural retina in LCA2 patients, offering a promising avenue for future clinical implementation.
Stress-specific expression of HSPA and DNAJ chaperones regulated by NRF2/HSF1 in neurodegenerative conditions.
Fatima S, Gupta A, Priya S
Mol Cell Biochem · 2026 Apr · PMID 41609899 · Publisher ↗
The cellular protein quality control and protein homeostasis is maintained by molecular chaperones that are upregulated in response to various environmental, chemical, thermal and genetic stress factors. Altered protein...
The cellular protein quality control and protein homeostasis is maintained by molecular chaperones that are upregulated in response to various environmental, chemical, thermal and genetic stress factors. Altered protein homeostasis owing to stress conditions lead to the accumulation of misfolded and aggregated protein conformers, a hallmark feature of several neurodegenerative and metabolic diseases. However, the effect of different stress conditions on the expression of molecular chaperones remains poorly understood. In the present study, comparative expression profile of the HSPA and DNAJ chaperone family has been analysed under oxidative stress induced by rotenone, proteotoxic stress induced by α-synuclein seeds, proteasome inhibitor and heat stress conditions. A dynamic and stress-selective expression of molecular chaperones was observed at both the gene and protein levels, where HSPA1 (HSP70), HSPA5 and DNAJB1 proteins were upregulated across all stress conditions, while HSPA8 (HSC70), HSPH1 (HSP110), DNAJB6 and DNAJB8 proteins exhibited stress-dependent unique expression patterns. The selective expression of molecular chaperones regulated through the NRF2/HSF1 axis suggests the involvement of the KEAP1/NRF2/ARE pathway in coordinating stress-dependent chaperone expression and ensuring proteome integrity. This comparative stress-specific expression profiling enables targeting of molecular chaperones to mitigate protein misfolding and aggregation, facilitating therapeutic interventions in neurodegenerative diseases.
Bioelectric fields drive pulmonary epithelial proliferation through PI3K/AKT/GSK3β signaling.
Shi C, Lu C, Lin C … +4 more , Lian S, Luo H, You Z, Li L
Mol Cell Biochem · 2026 Apr · PMID 41609898 · Publisher ↗
Defective alveolar re-epithelialization following acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represents a critical barrier to clinical recovery. Intrinsic signals that could be harnessed to sp...
Defective alveolar re-epithelialization following acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represents a critical barrier to clinical recovery. Intrinsic signals that could be harnessed to speed this repair remain poorly defined. Endogenous electric fields (EFs) arise immediately after epithelial injury and are recognized as mediators of cell migration and morphogenesis, but their impact on lung epithelial proliferation is unknown. Here we demonstrate that physiological-strength direct-current EFs (100–200 mV/mm) are potent pro-mitogenic signals for both human bronchial (BEAS-2B) and murine alveolar (MLE-12) epithelial cells. Within a custom live-cell electrotactic chamber, EFs exposure for 4 h doubled EdU incorporation, increased Ki-67 expression, and elevated real-time mitotic events without altering spindle orientation. RNA-seq analysis of BEAS-2B cells with EFs exposure identified 1,447 differentially expressed genes, with significant enrichment of the PI3K/AKT signaling pathway and immunoblotting further confirmed rapid phosphorylation of PI3K p85 (Tyr458)/p55 (Tyr199) and AKT (Ser473). Selective inhibition with Alpelisib or LY294002 abolished pathway activation and fully suppressed the pro-proliferative effect of EFs. Furthermore, EFs triggered AKT-dependent phosphorylation of glycogen synthase kinase-3β (GSK3β) at Ser9, while blockade with the GSK3β inhibitor Tideglusib or upstream PI3K inhibitors suppressed this event and attenuated EF-induced proliferation. Taken together, our findings delineate the PI3K/AKT/GSK3β signaling axis through which EFs enhance pulmonary epithelial proliferation. This work identifies physiological EFs as previously unrecognized regenerative cues in the lung and underscores bioelectric modulation as a promising therapeutic strategy to accelerate alveolar repair in ALI/ARDS.
CCL25/CCR9-induced M2 macrophage polarization promotes lung cancer progression via TGF-β1-mediated activation of the JAK/STAT-PIM2 signaling pathway.
Wen Q, Yuan Y, Liu Z … +2 more , Wang L, Pan C
Mol Cell Biochem · 2026 Apr · PMID 41604123 · Publisher ↗
Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. While the chemokine CCL25 is implicated in the tumor microenvironment, its specific role in LC is not fully understood. Here, we identify CCL25 a...
Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. While the chemokine CCL25 is implicated in the tumor microenvironment, its specific role in LC is not fully understood. Here, we identify CCL25 as a key promoter of tumor progression through a novel macrophage-mediated signaling axis. Bioinformatics and clinical analyses revealed that CCL25 is highly expressed in LC and correlates with M2 macrophage infiltration and poorer patient survival. In vitro, tumor-derived CCL25 drove M2 polarization of macrophages by upregulating its receptor CCR9. Functionally, these CCL25-CCR9-induced M2 macrophages secreted TGF-β1 and significantly enhanced the proliferation, migration, and invasion of LC cells. Mechanistically, this effect was mediated through the activation of the JAK/STAT signaling pathway and the subsequent upregulation of the downstream oncogene PIM2 in tumor cells. Both pharmacological inhibition of JAK/STAT and genetic knockdown of PIM2 reversed the tumor-promoting crosstalk. Single-cell transcriptomics confirmed the presence of a TGF-β1-expressing CCR9+ M2 macrophage subset in human tumors and revealed co-expression of CCR9 and PIM2 in tumor cells. In vivo, CCL25 overexpression accelerated tumor growth and M2 macrophage infiltration. Collectively, our findings define a complete CCL25-CCR9-TGF-β1-JAK/STAT-PIM2 signaling circuit wherein tumor cells educate macrophages to, in turn, fuel their own malignant progression, highlighting this axis as a potential therapeutic target in lung cancer.
Circadian rhythm and the molecular clock in endothelial function of the cardiovascular system.
Jiang Y, Li T, Tian Y … +6 more , Jia B, Gu C, Zhang T, Yang Y, Zhang Q, Yu G
Mol Cell Biochem · 2026 Apr · PMID 41604122 · Publisher ↗
All living organisms on Earth have evolved an internal, self‑sustained circadian rhythm that enables them to anticipate daily environmental changes driven by the 24‑hour rotation of our planet. However, modern lifestyle...
All living organisms on Earth have evolved an internal, self‑sustained circadian rhythm that enables them to anticipate daily environmental changes driven by the 24‑hour rotation of our planet. However, modern lifestyle disruptions, including increased competitiveness and excessive work pressure, significantly disturb circadian rhythms and sleep-wake cycles, contributing to various diseases and posing a major public health concern. Cardiovascular disease (CVD) is a highly prevalent condition and the leading cause of death worldwide. Acute CVD events exhibit distinct diurnal patterns, occurring most frequently in the early morning after awakening and showing a secondary, smaller peak in the late afternoon. The endothelium, a single layer of cells lining the inner surface of blood vessels, is a key regulator of vascular homeostasis. Numerous clinical studies have observed that endothelial function shows diurnal oscillations, being lowest in the morning and highest at night, while circadian misalignment is associated with endothelial dysfunction. However, the underlying mechanisms remain poorly understood. In this review, we show that major circadian clock components play distinct roles in regulating endothelial function, particularly through the modulation of eNOS/NO pathway. In addition, conventional pathways involving inflammation, lipid metabolism, macrophage activity, and oxidative stress participate in the circadian regulation of endothelial physiology, although their precise mechanisms and the specific circadian clock elements involved remain unclear. These findings may help identify new pathways to reduce the global burden of endothelial dysfunction and its related diseases. Meanwhile, although governments and health organizations have recognized the strong link between disrupted circadian rhythms and human disease, and emphasized the need to incorporate circadian biology into clinical practice and public health strategies, much remains to be learned about how circadian rhythms regulate endothelial function and how circadian disruption induces endothelial dysfunction and associated disorders.
Hsa_circ_0002103 promotes progression of colorectal cancer via miR-193a-3p/CCND1 axis.
Chen Y, Liu Y, Chen H … +1 more , Li H
Mol Cell Biochem · 2026 Mar · PMID 41591629 · Publisher ↗
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, with poor prognosis due to late diagnosis. Circular RNAs (circRNAs) are emerging as important regulators in cancer progression. This study in...
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths, with poor prognosis due to late diagnosis. Circular RNAs (circRNAs) are emerging as important regulators in cancer progression. This study investigates the role of hsa_circ_0002103/miR-193a-3p/CCND1 axis in CRC cells, focusing on its regulation of tumor growth, metastasis, and immune evasion. Bioinformatics analysis identified differentially expressed circRNAs (DECs) and miRNAs (DEMs) and constructed the circRNA-miRNA-target gene network in CRC. The hsa_circ_0002103/miR-193a-3p/CCND1 axis was validated using RIP, RNA pulldown, and dual-luciferase assays. Functional experiments assessed the effects on CRC cell proliferation, migration, invasion, and immune evasion. The expression of hsa_circ_0002103 was significantly increased in CRC cells, where it acted as a sponge for miR-193a-3p and promoted CCND1 expression. Hsa_circ_0002103 silencing inhibited the proliferation, migration, and invasion of CRC cells. These effects were reversed by the inhibition of miR-193a-3p. Furthermore, the axis modulated key immune-related factors by reducing the secretion of TNF-α and IFN-γ and upregulating PD-L1. The hsa_circ_0002103/miR-193a-3p/CCND1 axis promotes CRC cell progression and modulates key mediators of immune evasion, representing a potential therapeutic target.
circSH3GL3 inhibits glioma progression and invasion via regulating the PI3K/AKT and Wnt/β-catenin signaling pathways by competitively binding with miR-21-5p.
Liu Y, Liu Z, Wang M … +9 more , Li Z, Yin X, Li Y, Zhang K, Li S, Wu J, Sun J, Jin F, Xin T
Mol Cell Biochem · 2026 Mar · PMID 41591628 · Publisher ↗
Circular RNAs (circRNAs) have been identified as vital regulators in a variety of cancers, including glioma.However, the role of circRNAs in glioma initiation and progression remains largely unclear. In this study, we in...
Circular RNAs (circRNAs) have been identified as vital regulators in a variety of cancers, including glioma.However, the role of circRNAs in glioma initiation and progression remains largely unclear. In this study, we investigated the expression profiles of circRNA in three paired samples of glioblastoma multiforme (GBM). Our findings revealed that circSH3GL3 is significantly downregulated in GBM tissues, and its downregulation is associated with the WHO grade and patient survival. Furthermore, our research demonstrated that elevated circSH3GL3 suppresses cell proliferation and invasion both in vitro and in vivo. Mechanistically, circSH3GL3 shares microRNA response elements with tissue inhibitor of metalloproteinase 3 (TIMP3) and smad family member 7 (SMAD7).The present study investigates the role of circSH3GL3 in glioma proliferation and invasion. It is demonstrated that circSH3GL3 competitively binds to miR-21-5p, thereby preventing the decrease in the levels of TIMP3 and SMAD7. These proteins subsequently regulate the PI3K/AKT and Wnt/β-catenin signaling pathways, respectively. These findings reveal the critical role of circSH3GL3 in inhibiting glioma proliferation and invasion via a ceRNA mechanism. The study concludes that circSH3GL3 is a valuable biomarker and therapeutic target for glioma patients.
Causal relationship between chronic kidney disease and senile cataract: a bidirectional two-sample Mendelian randomization study.
Jin S, Huang J, Wang Y … +2 more , Ni Z, Zou H
Mol Cell Biochem · 2026 Apr · PMID 41591627 · Publisher ↗
Despite observed epidemiological associations, the direct causality between chronic kidney disease (CKD) and senile cataract remains unclear. This bidirectional Mendelian randomization (MR) study assessed the causal asso...
Despite observed epidemiological associations, the direct causality between chronic kidney disease (CKD) and senile cataract remains unclear. This bidirectional Mendelian randomization (MR) study assessed the causal associations between CKD-including glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), dialysis, and rapid eGFR decline-and senile cataract. Summary statistics from genome-wide association studies (GWAS) of European ancestry were analyzed. Data for senile cataract comprised 404,086 individuals, while data for CKD and related kidney function traits were sourced from large-scale meta-analyses (sample size up to 1,004,040). Instrumental variables with F-statistics greater than 10 were utilized to estimate causality via inverse-variance weighted (IVW) regression, complemented by weighted median, weighted mode, and MR-Egger methods. Sensitivity analyses included MR-PRESSO for pleiotropy adjustment and Cochran's Q for heterogeneity assessment. Additionally, a multivariable MR (MVMR) analysis was conducted to adjust for type 2 diabetes (T2D). Univariable MR analyses did not support causal relationships between general CKD, eGFR, UACR, or dialysis and senile cataract. However, in the MVMR analysis adjusting for T2D, a genetically predicted rapid eGFR decline (Rapid3) was significantly associated with an increased risk of senile cataract (OR = 1.089, P = 0.014). Reverse MR analyses indicated no causal effect of senile cataract on CKD or kidney function traits. This study found no evidence for a direct causal link between general CKD and senile cataract. However, the findings suggest that rapid deterioration of kidney function may be a causal risk factor for cataract, independent of shared genetic pathways with T2D. These results underscore the clinical importance of monitoring ocular health in patients experiencing accelerated kidney function loss.
High copper levels induce oxidative stress and inflammatory processes in a cell culture model of Wilson's disease.
Sasula MJ, Held ATJ, Schefczyk S … +4 more , Krawczyk M, Zibert A, Schmidt HH, Broering R
Mol Cell Biochem · 2026 Mar · PMID 41569496 · Full text
Wilson’s disease (WD) is a genetic disorder resulting from mutations in the ATP7B gene that lead to copper overload in hepatocytes. To gain a deeper understanding of the cellular mechanisms underlying WD, a reanalysis of...
Wilson’s disease (WD) is a genetic disorder resulting from mutations in the ATP7B gene that lead to copper overload in hepatocytes. To gain a deeper understanding of the cellular mechanisms underlying WD, a reanalysis of the GSE1073236 dataset was conducted and validated by comparative analyses in a cell culture model of HepG2 and HepG2 ATP7B knockout (ATP7B-KO) cells, as well as in primary hepatocytes from WD patients and controls. Increased expression levels of genes associated with autophagy, oxidative stress and inflammation were observed in copper-treated HepG2 ATP7B-KO cells and in primary hepatocytes from patients with WD. Furthermore, copper increased the secretion of IL1B, TNF, GM-CSF, and IL8 in HepG2 ATP7B-KO cells. Accordingly, copper exposure enhanced NFKB promoter activity 6 h after treatment. However, the transcriptional activity of AP1 and NFKB was reduced in these cells 24 h after treatment with 0.6mM CuCl2. In addition, both HepG2 and HepG2 ATP7B-KO cells showed increased oxidative stress and H2O2 levels after copper treatment, indicating that reactive oxygen species could play a role in WD. In the WD cell culture model, critical mechanisms behind copper-related cell death highlight the importance of this model in developing molecular targets for future therapeutic strategies.
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