BackgroundTriple‐negative breast cancer (TNBC) remains a major clinical challenge because of its aggressive characteristics, limited targeted treatment options, and frequent chemoresistance. However, the molecular mechanisms governing protein stability that drive TNBC progression and therapeutic resistance remain incompletely understood.MethodsTMEM92 expression and clinical relevance were evaluated using public datasets, patient specimens, and TNBC cell models. Loss‐of‐function, rescue, xenograft, protein interaction, and ubiquitination assays were performed to determine the biological function and molecular mechanism of TMEM92 in TNBC progression and cisplatin response.ResultsTMEM92 was prominently expressed in TNBC and correlated with poor prognosis. Functionally, depletion of TMEM92 suppressed TNBC cell proliferation, migration, invasion, and survival while promoting apoptosis in vitro and in vivo. Mechanistically, TMEM92 directly associated with DEAD‐box helicase 3 X‐linked (DDX3X) and protected it from degradation by the E3 ubiquitin ligase tetratricopeptide repeat domain 3 (TTC3). TMEM92 competitively prevented TTC3 binding to DDX3X, thereby inhibiting TTC3‐mediated K48‐linked ubiquitination and subsequent proteasomal degradation of DDX3X. Re‐expression of DDX3X rescued the anti‐tumor effects induced by TMEM92 knockdown. Therapeutically, TMEM92 targeting sensitized TNBC cells and xenograft tumors to cisplatin. TMEM92 knockout reduced the cisplatin IC50 by 44.0% in MDA‐MB‐231 cells and 42.9% in BT‐549 cells, and TMEM92 depletion enhanced cisplatin‐induced tumor growth inhibition by approximately 70.6% compared with cisplatin alone.ConclusionsThis study identifies a novel TMEM92DDX3XTTC3 axis that regulates DDX3X protein stability and drives TNBC progression and chemoresistance, revealing a potential prognostic and therapeutic vulnerability in TNBC.

BackgroundMetabolic dysfunction–associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver‐related mortality, yet no therapies directly target fibrosis in the later stages of the disease. Fibroblast growth factor 10 (FGF10) facilitates epithelial repair, yet its function and epithelial receptor requirements in chronic liver fibrogenesis are unclear.MethodsWe quantified hepatic FGF10 and fibroblast growth factor receptor 2 (FGFR2) expression across fibrosis stages in biopsies from patients with MASLD and mouse models. We then augmented hepatic FGF10 using adeno‐associated virus‐mediated liver expression or subcutaneous recombinant human FGF10 in carbon tetrachloride (CCl4) and high‐fat diet plus CCl4‐induced advanced fibrosis. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms.ResultsHepatic FGF10 and FGFR2 protein expression were significantly reduced at advanced disease stages. Restoring FGF10 led to regression‐associated remodelling of established bridging fibrosis, a decrease in inflammatory cytokines and a reduction in hepatocyte apoptosis, even with continued CCl4 exposure, indicating histologic regression rather than slowed progression. These therapeutic effects required hepatocyte FGFR2, as hepatocyte‐specific FGFR2 deletion abolished protection and the associated transcriptional reprogramming of matrix and cytokine networks. In primary hepatocytes, FGF10 activated FGFR2–FGFR substrate 2α (‌FRS2α) signalling, increased inhibitory phosphorylation of glycogen synthase kinase 3β at Ser9 and suppressed nuclear factor kappa B, thereby lowering transforming growth factor β1 and other cytokines and indirectly limiting HSC activation. The efficacy extended to a high‐fat diet plus CCl4 model of steatohepatitis.ConclusionsThese findings elucidate a hepatocyte‐centric FGF10–FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte‐targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression‐associated architectural remodelling in advanced liver fibrosis.Key pointsHepatic FGF10 and FGFR2 decline consistently with fibrosis stage in patient liver biopsies and complementary mouse models.Restoring FGF10 through AAV‐Fgf10 or recombinant FGF10 reduces hepatocyte apoptosis, inflammation and extracellular matrix deposition.Hepatocyte FGFR2 is required for FGF10‐mediated antifibrotic effects and drives transcriptional reprogramming that limits fibrogenesis.

Traumatic spinal cord injury (SCI) induces a robust local inflammatory response that can both facilitate repair and exacerbate pathology. Hydroxycarboxylic acid receptor 2 (Hcar2) is known to exert immunomodulatory effects; however, its role in SCI and its potential for targeting Hcar2 to alleviate motor deficits remain unclear. The spinal cord transcriptome following SCI, with a focus on Hcar2, was analysed via publicly available single-cell RNA sequencing datasets from mice and rhesus macaques. Additionally, an in vivo SCI mouse model with Hcar2 knockout and an in vitro LPS-induced BV2 microglial model were established to assess Hcar2 gene and protein expression, microglial activation and inflammatory responses via bulk RNA sequencing, immunofluorescence staining, Western blotting, and real-time polymerase chain reaction. To evaluate the protective effects of Hcar2 activation, niacin, a known Hcar2 agonist, was administered to mice or BV2 cells, followed by assessments of the inflammatory response and motor function. Hcar2 gene expression, which was enriched predominantly in spinal cord microglia, was upregulated following SCl, peaking at 7 days post-SCl. Genetic knockout of Hcar2 decreased the percentage of impaired anti-inflammatory polarized microglia and increased the inflammatory response. In contrast, Hcar2 activation with niacin in LPS-stimulated microglia BV cell models reversed mitochondrial dysfunction, increased the oxygen consumption rate and reduced the expression of the cytokines IL-6 and IL-1β. The administration of niacin to SCl mice upregulated anti-inflammatory microglia, reduced the expression of multiple proinflammatory cytokines, increased the number of motor neurons and improved motor function recovery. Notably, all these protective effects were abolished by genetic loss of Hcar2. Hcar2 serves as a critical regulator of microglial polarization, promoting the switch from a proinflammatory phenotype to an anti-inflammatory phenotype through immunometabolic reprogramming. Targeting Hcar2 with niacin may offer a translatable therapeutic strategy to improve functional recovery after SCl. Hcar2 is identified as a conserved, injury-induced metabolic checkpoint specifically enriched in microglia following spinal cord injury. Hcar2 activation reprogrammes microglial metabolism from glycolysis to oxidative phosphorylation to drive reparative anti-inflammatory polarization. Pharmacological targeting of Hcar2 with niacin resolves neuroinflammation and promotes functional motor recovery in an Hcar2-dependent manner.

BackgroundKinesin family member 23 (KIF23) is recognised as an important tumour promoter involved in the pathogenesis of various cancers. However, its role and underlying molecular mechanisms in regulating cervical cancer (CC) growth and primary chemoresistance remain to be fully elucidated.MethodsThe expression and prognostic significance of KIF23 were initially assessed through bioinformatic analyses and subsequently validated in clinical specimens. To evaluate the effects of KIF23 on cell proliferation and cisplatin (DDP) sensitivity in CC cells, in vitro and in vivo experiments were conducted using CRISPR/Cas9 knockout, overexpression and mouse xenograft models. Co‐immunoprecipitation, protein half‐life assays and ubiquitination assays were employed to elucidate the interactions and regulatory mechanisms involving KIF23, myosin heavy chain 9 (MYH9), minichromosome maintenance protein 2 (MCM2) and proliferating cell nuclear antigen (PCNA), thereby revealing the molecular basis of KIF23‐mediated CC progression and primary chemoresistance.ResultsKIF23 is highly expressed in CC tissues and is significantly correlated with poor prognosis and DDP resistance in patients. The knockout of KIF23 inhibited cell proliferation, induced G1‐phase arrest and enhanced chemosensitivity to DDP. Mechanistically, the C‐terminal domain of KIF23 was found to directly bind to the myosin tail domain of MYH9. This interaction stabilises MYH9 by recruiting deubiquitinase 7 (ubiquitin‐specific protease 7 [USP7]), which removes K48‐linked ubiquitin chains. The consequent upregulation of MYH9 promoted the recruitment of ubiquitin‐specific protease 15 (USP15) to deubiquitinate MCM2, thereby preventing its degradation. Lysine 469 (K469) of MCM2 was identified as the key site for MYH9‐induced deubiquitination. Furthermore, elevated MCM2 levels enhanced its binding to PCNA, thereby promoting CC cell proliferation.ConclusionsThese findings demonstrated that elevated KIF23 levels act as an unfavorable prognostic factor for CC by promoting cell proliferation and primary chemoresistance via the activation of the MYH9/MCM2/PCNA axis. Thus, KIF23 may represent a promising therapeutic target for improving clinical outcomes in CC.HighlightsCisplatin treatment induces KIF23 expression in a concentration‐ and time‐dependent manner.KIF23 recruits USP7, which removes the K48‐linked ubiquitin chain of MYH9, thereby stabilising MYH9 and facilitating its nuclear transport.MYH9 recruits USP15, thereby stabilising MCM2, which, in turn, regulates the G1/S phase transition by binding to PCNA.Targeting the KIF23/MYH9/MCM2/PCNA axis sensitises cervical cancer cells to cisplatin.

BackgroundUrothelial carcinoma (UC) is a biologically heterogeneous disease, and current molecular classifications have limited integration into clinical decision‐making. To further pursue precision oncology efforts in UC, we developed a molecular classification framework applicable to transcriptomic and proteomic data from non–muscle‐invasive bladder cancer (NMIBC), muscle‐invasive bladder cancer (MIBC) and urothelial cancer cell lines.MethodsUsing a whole‐transcriptome self‐organised map and regularised semi‐supervised clustering of 4439 bulk NMIBC and MIBC transcriptomes and proteomes, and 33 UC cell lines, we identified three molecular UC clusters. Making use of both in silico and in vitro approaches, we selected promising treatment approaches for each cluster.ResultsThe three developed clusters displayed distinct signatures of mRNA, proteins, biological processes, metabolism and essential driver genes. They also differed in prognosis and machine learning‐predicted treatment vulnerabilities and resistance. High‐risk, stroma‐rich Cluster #1 cancers were predicted to respond to selected cytotoxic drugs, ferroptosis inducers and PARP inhibitors. For the aggressive, fast‐proliferating, immune‐infiltrated Cluster #2 tumours with basal/squamous differentiation, cytotoxic agents and EGFR/ERBB‐ and MEK/ERK‐targeting therapies were proposed. Cluster #3 cancers of predominantly luminal papillary phenotype with scarce stroma and immune infiltration were enriched with NMIBC and low‐risk malignancies. For patients with Cluster #3 tumours, selected epigenetic drugs or EGFR/FGFR inhibitors may represent attractive treatment options.ConclusionsOur novel molecular taxonomy holds promise as a practical framework for patient risk stratification and clinical trials in UC. Our molecular classification scheme may facilitate personalised transcriptome‐ and proteome‐based risk assessment and clinical trial design for the development of various therapeutics.key pointsWe developed three UC clusters, applicable for MIBC and NMIBC, which were validated using transcriptomic- and proteomic datasets.Publically available UC cell lines were assigned to the clusters, to have in vitro models representing each cluster.The clusters differ in molecular and biological signatures, with distinct prognostic and therapeutic characteristics.