Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), yet radioresistance frequently develops and leads to the failure of treatment for NPC. NSUN2 acts as a potential oncogene in NPC, but its role in...Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), yet radioresistance frequently develops and leads to the failure of treatment for NPC. NSUN2 acts as a potential oncogene in NPC, but its role in NPC radioresistance remains unclear. In this study, we revealed that NSUN2 was upregulated in radioresistant NPC tissues. Through a series of functional assays following radiotherapy, including CCK-8, colony formation, apoptosis analysis by flow cytometry, we demonstrated that NSUN2 promoted radioresistance and enhanced DNA damage repair in NPC cells. Mechanistically, NSUN2 negatively regulated TP53 expression and competitively enhanced the UCHL3-RAD51 interaction, thereby facilitating RAD51 deubiquitination and RAD51-mediated homologous recombination repair of DNA double-strand breaks. Moreover, the suppressive effect of NSUN2 knockdown on NPC radioresistance was reversed by TP53 knockdown. Furthermore, the small molecule GSK-F1 was found to directly bind to NSUN2 and promote its proteasomal degradation, consequently activating the downstream TP53/RAD51 signaling axis and increasing NPC cell cytotoxicity and radiosensitivity. In conclusion, our study elucidates that NSUN2 promotes NPC radioresistance by negatively regulating the TP53/RAD51 axis, and the NSUN2 inhibitor GSK-F1 functions as a radiosensitizer in NPC by disrupting the NSUN2/TP53/RAD51 signaling pathway, thereby providing a potential clinical strategy for the targeted therapy and radiosensitivity in NPC.
Glioblastoma (GBM) is a highly aggressive malignancy characterized by dysregulated cell proliferation and impaired stress-response control. Here, we identify the E3 ubiquitin ligase TRIM47 as a regulator of p53 proteosta...Glioblastoma (GBM) is a highly aggressive malignancy characterized by dysregulated cell proliferation and impaired stress-response control. Here, we identify the E3 ubiquitin ligase TRIM47 as a regulator of p53 proteostasis and proliferative signaling in GBM. Integrated bioinformatic analyses and immunohistochemistry revealed that TRIM47 is upregulated in GBM and associated with unfavorable survival. Functional assays demonstrated that TRIM47 depletion suppressed GBM cell proliferation and clonogenic growth, induced G1-phase arrest, and markedly inhibited intracranial tumor growth . Mechanistically, TRIM47 interacted with p53 through its RING-containing region and promoted K48-linked ubiquitination predominantly at lysine 319, leading to proteasome-dependent degradation of p53. Loss of TRIM47 results in stabilization of p53 protein, activation of p21, accumulation of DNA damage, and attenuation of cell-cycle progression. In GBM models exposed to temozolomide-induced genotoxic stress, TRIM47 expression was reduced whereas p53 signaling and DNA damage markers were elevated. Moreover, inhibition of PDK1 kinase activity impaired TRIM47-mediated p53 ubiquitination and enhanced p53-dependent stress responses. Collectively, these findings establish TRIM47 as a critical regulator of p53 proteostasis and cell-cycle progression in GBM, thereby maintaining proliferative fitness under genotoxic stress.
Genetic predisposition and unhealthy lifestyles are well-known contributors to disorders of glucose and lipid metabolism, including type 2 diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. Howe...Genetic predisposition and unhealthy lifestyles are well-known contributors to disorders of glucose and lipid metabolism, including type 2 diabetes, obesity, and metabolic dysfunction-associated fatty liver disease. However, these factors alone cannot fully explain the rapidly rising prevalence of these conditions. Emerging evidence highlights the pivotal role of the intrauterine environment in gestational diabetes mellitus (GDM) in shaping epigenetic modifications and metabolic reprogramming, thereby predisposing offspring to long-term metabolic complications. Exosomes have recently been identified as key mediators of maternal-fetal communication. In GDM, both the quantity and cargo (e.g., proteins, miRNAs) of exosomes are altered. These altered exosomes not only contribute to maternal glucose and lipid metabolic abnormalities but also act as a critical vector for transmitting adverse metabolic signals to the offspring. This exosome-mediated communication disrupts placental function and the development of fetal metabolic organs, ultimately programming the offspring for long-term metabolic disorders. In this review, we summarize the characteristic changes of maternal exosomes in GDM and explore the potential mechanism by which exosomes regulate offspring metabolism during maternal-fetal crosstalk. We also propose the possible direction of exosomes in application, providing insights into early-life strategies for the prevention of metabolic diseases.
Resistance to first-line multikinase inhibitors (MKIs) sorafenib and lenvatinib critically limits hepatocellular carcinoma (HCC) treatment efficacy. It remains largely unknown how long non-coding RNAs (lncRNAs) affect re...Resistance to first-line multikinase inhibitors (MKIs) sorafenib and lenvatinib critically limits hepatocellular carcinoma (HCC) treatment efficacy. It remains largely unknown how long non-coding RNAs (lncRNAs) affect resistance to MKIs. Through integrated analysis of resistant HCC models, we identified lncRNA LMCD1-AS1 as a critical driver of MKI resistance. LMCD1-AS1 overexpression correlates with advanced tumor stage, shortened survival, and resistance to MKI therapy in HCC patients. LMCD1-AS1 confers dual resistance to sorafenib and lenvatinib by suppressing apoptosis, while its knockdown restored drug sensitivity. Mechanistically, LMCD1-AS1 directly bind histone demethylase PHF8, promoting H4K20me1 to epigenetically activate oncogenes (e.g., c-Myc, β-catenin) and upregulate lactate dehydrogenase A (LDHA). This triggers lactate overproduction and alters the NAD/NADH ratio, establishing a protumorigenic metabolic state. Crucially, PHF8 ablation reverses LMCD1-AS1-driven resistance, and xenografts confirm attenuated sorafenib efficacy with LMCD1-AS1 overexpression. Our work unveils the LMCD1-AS1/PHF8/H4K20me1 axis as a unified epigenetic-metabolic mechanism underlying MKI resistance, representing a promising therapeutic target and prognostic biomarker for HCC.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown mechanism and without effective drugs. The mechanisms involved in the progression of IPF are multifactorial, among which the conversio...Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown mechanism and without effective drugs. The mechanisms involved in the progression of IPF are multifactorial, among which the conversion of biochemical signal to mechanical force has not been studied. Investigating the mechanism underlying IPF pathogenesis is essential for developing therapeutic approaches. The study aimed to investigate the mechanism of circELP2-mediated mechanical forces through YAP1. Mechanistic dissection clarified that circELP2 binds with the 217-307 amino acid fragment of TRIM25 to promote TRIM25 deacetylation at K447 site, which facilitates phase separation formation of TRIM25 via its 370-401 amino acid fragment. Then, TRIM25 strengthens ubiquitin-dependent degradation of 14-3-3ζ, which results in the target gene YAP1 of 14-3-3ζ translocation from the cytoplasm to the nucleus. Nuclear YAP1 drives the super-enhancer formation on the cytoskeleton gene locus to initiates the transcription of cytoskeleton remodeling genes, leading to amplifying mechanical forces. Consequently, the condition accelerates fibroblast-to-myofibroblast differentiation to promote pulmonary fibrosis. These findings confirm that YAP1 converts circELP2-mediated biochemical signals to mechanical forces through promoting cytoskeleton remodeling in pulmonary fibrosis. Targeting circELP2 can mitigate pulmonary fibrogenesis which is a mechanical force-related therapeutic target for IPF.
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Intestinal homeostasis relies on the intricate ba...Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Intestinal homeostasis relies on the intricate balance of cell fate decisions within the intestinal epithelium and immune compartments. Ubiquitin-modifying enzymes (UMEs), including E2 conjugating enzymes, E3 ubiquitin ligases, and deubiquitinating enzymes (DUBs), have emerged as pivotal molecular regulators of these processes by orchestrating post-translational modifications that dictate protein stability, activity, and localization. In this review, we systematically summarize the essential roles of UMEs in modulating diverse cell-fate outcomes and their subsequent effects on intestinal barrier integrity and immune responses. Furthermore, we discuss the pathogenic dysregulation of specific UMEs in IBD and highlight their potential as diagnostic biomarkers and therapeutic targets. Finally, we explore emerging strategies, including small-molecule inhibitors and PROTAC technology, for targeting UMEs in clinical applications. By integrating current advances, this review provides novel insights into the ubiquitin-mediated regulation of intestinal cell fate and offers new perspectives for the management of IBD and the prevention of colitis-associated cancer (CAC).
Epidermal growth factor receptor (EGFR) is a pivotal therapeutic target in pancreatic ductal adenocarcinoma (PDAC); however, the clinical efficacy of tyrosine kinase inhibitors (TKIs) such as erlotinib is frequently curt...Epidermal growth factor receptor (EGFR) is a pivotal therapeutic target in pancreatic ductal adenocarcinoma (PDAC); however, the clinical efficacy of tyrosine kinase inhibitors (TKIs) such as erlotinib is frequently curtailed by acquired resistance. This study identifies histone deacetylase 1 (HDAC1) as a critical epigenetic driver of this resistance. HDAC1 is markedly upregulated in erlotinib-resistant PDAC cells, where it directly suppresses the transcriptional activity of TFCP2 through site-specific deacetylation at lysine 256 (K256). This modification attenuates TFCP2 function, leading to transcriptional repression of the metastasis suppressor NDRG1 and increased expression of EGFR, thereby activating EGFR-TKI resistance signaling pathways. Furthermore, EGFR-mediated tyrosine phosphorylation protects HDAC1 from ubiquitin-proteasome system (UPS)-dependent degradation, stabilizing HDAC1 and establishing a self-reinforcing feedback loop that sustains its elevated expression in the resistant state. To counter this mechanism, we designed a bioactive peptide derived from TFCP2 that competitively inhibits K256 deacetylation, thereby restoring TFCP2 transcriptional activity. In and in studies demonstrate that pharmacological inhibition of HDAC1 or restoration of TFCP2 acetylation reverses erlotinib resistance in PDAC. These findings unveil a previously unrecognized mechanism of EGFR-TKI resistance and suggest a promising strategy to enhance therapeutic efficacy in PDAC.
Skeletal muscle's ability to perceive and adapt to physical force is fundamental to tissue homeostasis and systemic health. At the core of this process, mechanosensitive ion channels (MSCs)-notably the Piezo and TRP fami...Skeletal muscle's ability to perceive and adapt to physical force is fundamental to tissue homeostasis and systemic health. At the core of this process, mechanosensitive ion channels (MSCs)-notably the Piezo and TRP families-function as primary transducers. This review synthesizes how these channels convert diverse mechanical stimuli into biochemical signals. We delineate how their activation, primarily through Ca2+ influx, engages downstream signaling hubs, including the Hippo-YAP/TAZ, MAPK, and PI3K-Akt-mTOR pathways. These cascades subsequently orchestrate muscle growth, regeneration, and metabolic remodeling. We then bridge these molecular mechanisms to clinical relevance, analyzing how physical therapies like low-intensity pulsed ultrasound and electrical stimulation precisely target these networks to enhance muscle repair. Furthermore, we explore the role of MSCs in driving skeletal muscle's function as an endocrine organ. Mechanical activation triggers myokine release, mediating critical inter-organ communication with bone, adipose, and immune systems. Collectively, this review establishes MSCs as pivotal molecular hubs that integrate external physical energy with local tissue repair and systemic physiological regulation.
Hepatic ischemia-reperfusion injury (HIRI) contributes to metabolic disorders within hepatic sinusoid and frequently occurs during liver transplantation, yet its underlying mechanisms and intervention strategies remain o...Hepatic ischemia-reperfusion injury (HIRI) contributes to metabolic disorders within hepatic sinusoid and frequently occurs during liver transplantation, yet its underlying mechanisms and intervention strategies remain obscure. This study aimed to elucidate whether acteoside (ACT) improved HIRI by repairing mitochondrial calcium uptake 1 (MICU1)-mediated Ca dysregulation and facilitating glycolytic reprogramming. Using RNA sequencing, cleavage under targets & tagmentation (CUT&Tag) analysis, liver sinusoidal endothelial cells (LSECs)-specific overexpression virus or siMicu1 lipid nanoparticles and ACT derivatives, we explored the hepatoprotective mechanisms of ACT in HIRI mice and in hypoxia-reoxygenation or lactate-stimulated LSECs. ACT enhanced endoplasmic reticulum function and restored mitochondrial homeostasis, thereby alleviating LSECs damage and HIRI. Mechanistically, ACT directly bound to MICU1 and inhibited the overflow of Ca from endoplasmic reticulum (ER) to mitochondria and subsequent mitochondrial Ca overload. This competitive binding mode also suppressed MICU1-dependent glycolysis by blocking Ca-stimulated lactate production and histone H3K18 lactylation, which epigenetically regulated MICU1 transcription. Notably, ACT synergized with lactate inhibitors or lipid nanoparticles to enhance its anti-HIRI effects, while LSECs-specific overexpression abolished these benefits. Structural analysis revealed that the C/C/C/C hydroxyl groups determined ACT's MICU1-binding and hepatoprotective activities. This study identifies MICU1 as a central regulator of HIRI and reveals ACT as a targeted therapy by restoring Ca balance and metabolic homeostasis.
Tumor evolution refers to the process by which a tumor develops and changes over time. Tumor evolution is a complex phenomenon that involves a series of stages and factors that contribute to tumor growth, progression and...Tumor evolution refers to the process by which a tumor develops and changes over time. Tumor evolution is a complex phenomenon that involves a series of stages and factors that contribute to tumor growth, progression and dissemination. These factors may include genetic mutations, changes in gene expression, interactions with the tumor microenvironment, and the immune system response. Tumor evolution can lead to the acquisition of characteristics that allow the tumor to evade the body's control mechanisms and become more aggressive. This may include the capacity for uncontrolled growth, invasion of surrounding tissues, metastasis formation, and resistance to therapy. Understanding tumor evolution is essential to develop more effective prevention, diagnosis and treatment strategies against cancer. Current research is actively studying the mechanisms involved in tumor evolution to identify new targeted therapies and treatment strategies that can address tumor heterogeneity and plasticity. In this review we provide an evolutive perspective of Cancer. From a Darwinian point of view, we present tumors as biological entities subject to similar traits to evolve and develop as natural species. This Darwinian process has strong effects in the clinical tumor as organism behavior, alone or after treatment. From understanding tumorigenesis to treatments, from cancer as disease in its interaction with the microenvironment to therapies; in this review we provide a biological perspective to better understand tumor evolution.
The integrity of the alveolar epithelial barrier is fundamental to pulmonary homeostasis, yet the molecular regulators governing its tight junction (TJ) dynamics remain incompletely understood. Here, we uncover a critica...The integrity of the alveolar epithelial barrier is fundamental to pulmonary homeostasis, yet the molecular regulators governing its tight junction (TJ) dynamics remain incompletely understood. Here, we uncover a critical, non-canonical function for FGFR1 as a master regulator of TJ homeostasis. We demonstrate that the RET inhibitor pralsetinib (Pral) induces fatal interstitial lung disease by inhibiting FGFR1, not RET, leading to the selective loss of occludin (OCLN). This disruption stems from transcriptional repression, mediated by the transcription factor CREB1. By integrating and studies, including lung epithelial-specific -knockout mice, we confirm that deficiency alone is sufficient to disrupt tight junctions, reduce OCLN expression, and trigger spontaneous lung injury. Our findings establish the FGFR1-CREB1-OCLN axis as a central regulator of TJ integrity, offering new therapeutic perspectives for lung diseases associated with TJ dysfunction.
Sarcopenic obesity (SO) is a complex condition involving increased fat accumulation along with reduced muscle mass and impaired muscle function; however, there are currently no approved pharmacological interventions targ...Sarcopenic obesity (SO) is a complex condition involving increased fat accumulation along with reduced muscle mass and impaired muscle function; however, there are currently no approved pharmacological interventions targeting these pathological features. Akt and AMPK are key signaling pathways regulating muscle homeostasis and energy metabolism. Natural compounds that modulate these pathways may offer a promising multi-targeted therapeutic strategy. This study investigated the effects of Fucoidan P on SO and its underlying molecular pathways, while assessing translational relevance using clinical datasets. Fucoidan P decreased body weight and fat mass and size while improving grip strength, muscle mass, and fiber size during high-fat diet feeding. Fucoidan P mitigated muscle atrophy through phosphorylation of Akt, mTOR, and FOXO3a, and enhanced energy metabolism by activating the AMPK/SIRT1/PGC-1α pathway. Moreover, Fucoidan P downregulated PDE5A and PTGS1, which are identified differentially expressed genes-related to inflammation of clinical datasets, and inhibited pro-inflammatory cytokines by suppressing NF-κB pathway. Taken together, these findings demonstrate that Fucoidan P alleviates SO by coordinately regulating muscle protein homeostasis, energy metabolism, and inflammatory responses through a network of interconnected Akt and AMPK/PGC-1α, and NF-κB signaling pathways, suggesting its potential as a multi-target therapeutic agent for SO.
BACKGROUND: Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen...BACKGROUND: Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen new therapeutic target is still lacking. METHODS: We established three inflammatory models based on olfactory epithelium (OE) organoids, using lipopolysaccharide (LPS), TNFα treatment and doxycycline induction. The efficacy of these models was evaluated by immunostaining, RNA sequencing, qPCR, and functional assays. RESULTS: These inflammatory organoid models mimicked impairment in cell proliferation and neuronal genesis, and showed upregulation of inflammation-related signaling pathway and downregulation of cell cycle-related pathway. We identified that DNA damage inducible transcript 3 (Ddit3) was upregulated in all inflammatory organoid models. Ddit3 downregulation counteracted apoptosis, alleviated cell proliferation and neuronal differentiation, and recovered the functional response to odor stimulation in all three inflammatory organoid models. Ddit3 deficiency counteracted effect of LPS instillation by promoting cell proliferation, recovering neurogenesis, attenuating inflammation, and improving electrophysiological response to odor mixes in the OE. Single-cell RNA sequencing analysis showed that Ddit3 upregulation in mature olfactory sensory neurons of inducible inflammation model and patients with aging-related olfactory dysfunction correlated with endoplasmic reticulum stress and neuron apoptotic process. CONCLUSIONS: We established olfactory inflammation organoid models, and made use of these models to identify Ddit3 as a potential therapeutic target against inflammation-related olfactory neuronal loss and functional deficit.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with limited therapeutic options. Dysregulated transcriptional networks are key drivers of its aggressive biology. Here, by integrating clinica...Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with limited therapeutic options. Dysregulated transcriptional networks are key drivers of its aggressive biology. Here, by integrating clinical datasets with mechanistic studies, we performed a family wide systematic analysis of E2F transcription factors and identified E2F3 as a key oncogenic driver with prognostic significance comparable to E2F1. Functional studies showed that E2F3 accelerates PDAC proliferation and xenograft growth. Mechanistically, E2F3 transcriptionally activates the E3 ligase TRIM26, which binds TAB1, promotes K11-linked polyubiquitination, and facilitates TAB1-TAK1 complex formation to engage canonical NF-κB signaling. The SPRY and RING domains of TRIM26 mediate TAB1 interaction and ubiquitination, respectively. TRIM26 depletion attenuated E2F3 induced NF-κB activation and tumor growth, whereas its restoration rescued these effects. Clinically, E2F3, TRIM26, and phosphorylated p65 levels were positively correlated in PDAC tissues, and therapeutic delivery of siTRIM26 recapitulated NF-κB inhibition. These findings uncover an unrecognized E2F3-TRIM26-TAB1/TAK1-NF-κB signaling axis that links cell cycle regulation with inflammatory activation in PDAC and nominate TRIM26 as a druggable vulnerability to therapeutically decouple this oncogenic crosstalk.
The HIV-1 envelope glycoprotein gp120 binds to the CD4 molecule and then undergoes conformational changes to interact with the co-receptors CCR5 or CXCR4, resulting in cellular entrance. However, certain types of cells,...The HIV-1 envelope glycoprotein gp120 binds to the CD4 molecule and then undergoes conformational changes to interact with the co-receptors CCR5 or CXCR4, resulting in cellular entrance. However, certain types of cells, such as macrophages and CD4Foxp3 regulatory T cells (Tregs), have been shown to resist HIV-1 infection despite co-expressing CD4 and co-receptors. In this study, we found that tumor necrosis factor receptor type II (TNFR2) directly binds to gp120, with the binding site on gp120 in proximity to that of CD4. Intriguingly, exogenous TNFR2 had the capacity to inhibit the binding of gp120 to CD4 T cells. Furthermore, the infection of CD4CCR5 cells by pseudoviruses containing the HIV-1 envelope was inhibited by TNFR2 protein. In contrast, TNFR1, which is structurally similar to TNFR2 and shares the same ligand, failed to inhibit the infection of CD4 T cells by HIV-1 pseudoviruses. This property of TNFR2 may be harnessed in the prevention or treatment of HIV-1 infection and thus warrants future investigation.
NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular ca...NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular carcinomas, it appears to act as a tumor promoter in breast and head and neck cancers. This study explored the role of NLRX1 in prostate cancer (PCa), examining its impact on cell proliferation, apoptosis, migration, invasion, and tumor progression, as well as associated molecular mechanisms. Using TCGA data, the association between NLRX1 expression and PCa prognosis was evaluated. NLRX1 expression was upregulated under serum-free stress conditions. Silencing NLRX1 reduced cell proliferation in PC3 cells, but not in LNCaP cells. Additionally, NLRX1 knockdown inhibited migration and invasion, while promoting apoptosis under serum-free conditions. Mechanistically, NLRX1 knockdown reduced AKT and ERK phosphorylation in response to serum deprivation, EGF, and TGF-β, without affecting PDK1 activity under serum deprivation. Pharmacological data showed AKT and ERK as key regulators of viability and invasion, with AKT critical for growth and migration. Co-immunoprecipitation, confocal microscopic examination, domain binding, structural modeling, and molecular dynamics revealed a stable interaction between NLRX1's LRR domain and AKT's PH domain. NLRX1 facilitated cell proliferation, migration, invasion, and resistance to serum-free stress through direct interaction with AKT, highlighting NLRX1 as a promising biomarker for PCa progression.
Given the lack of effective targeted therapeutic options for triple-negative breast cancer (TNBC), there is an imperative demand for innovative treatment approaches, with ferroptosis standing out as a promising direction...Given the lack of effective targeted therapeutic options for triple-negative breast cancer (TNBC), there is an imperative demand for innovative treatment approaches, with ferroptosis standing out as a promising direction. This study identifies HSPA6 as a key ferroptosis sensitizer in TNBC. Mechanistically, HSPA6 binds to NF-κB p65, inhibits its nuclear translocation and Ser468 phosphorylation, thereby suppressing transcription of the lipogenic enzyme FASN and downregulating phospholipid-remodeling enzymes LPCAT1/cPLA2. This dual inhibition enriches membrane phospholipids with polyunsaturated fatty acids, heightening peroxidation susceptibility and triggering ferroptosis. Concurrently, HSPA6-mediated suppression of lipogenesis depletes palmitate, thereby attenuating ANKIB1 palmitoylation and inhibiting its E3 ligase activity. This impairs K48-linked ubiquitination and degradation of HSPA6, forming a stabilizing positive feedback loop. Our study uncovers a HSPA6-p65-FASN-ANKIB1 axis linking lipid metabolism to ferroptosis, offering a novel TNBC therapeutic target.
Hepatocellular carcinoma (HCC) is associated with high mortality due to late diagnosis, recurrence, and limited therapeutic options. Thus, there is an urgent need for novel treatment approaches and new therapeutic target...Hepatocellular carcinoma (HCC) is associated with high mortality due to late diagnosis, recurrence, and limited therapeutic options. Thus, there is an urgent need for novel treatment approaches and new therapeutic targets. Cardiotoxicity resulting from anticancer therapies has become increasingly prominent, leading to a higher risk of cardiovascular diseases among cancer survivors. In our study, through a drug library screening, we identified that the cardiovascular therapeutic agent nebivolol exerts antitumor effects against HCC both and . Mechanistically, nebivolol suppressed HCC progression by downregulating RHOQ independently of β-adrenergic receptors. Furthermore, the combination of nebivolol and lenvatinib synergistically inhibited HCC proliferation both and . This study provides a rationale for repurposing nebivolol as a combination strategy for HCC therapy.