Cytoskeletal protein KRT14 governs cisplatin resistance by modulating eIF4H-dependent ACOX2 translation and lipid metabolism in bladder cancer.

Cisplatin-based chemotherapy remains a mainstay for the treatment of bladder cancer (BLCA); however, its clinical efficacy is frequently compromised by the emergence of chemoresistance, which leads to poor patient outcomes. Although known mechanisms-such as alterations in drug efflux, DNA repair, and key signaling pathways-have been implicated, they fail to fully explain the clinical complexity of cisplatin resistance, indicating that additional molecular drivers remain undiscovered. Keratin 14 (KRT14), an intermediate filament protein associated with aggressive BLCA subtypes, is consistently upregulated in cisplatin-resistant tumors, yet its precise mechanistic role in resistance remains unclear. In this study, we elucidate the functional contribution of KRT14 to cisplatin resistance in BLCA using patient-derived tissues, established cell lines, xenograft mouse models, and a suite of molecular interaction assays. Our results demonstrate that KRT14 is significantly upregulated in BLCA tissues, correlates with poor clinical prognosis, and functionally drives cisplatin resistance both in vitro and in vivo. Mechanistically, we identify a novel and direct interaction between KRT14 and the translation initiation factor eIF4H, specifically through the N-terminal Head domain of KRT14. This interaction modulates the association of eIF4H with the core eIF4F complex, thereby selectively promoting the translation of Acyl-CoA Oxidase 2 (ACOX2) mRNA through its 5' untranslated region. We further show that ACOX2 is essential for mediating the effects of KRT14 on lipid metabolism, cell proliferation, survival, and ultimately, cisplatin resistance. Collectively, our findings reveal that KRT14 contributes to chemoresistance in BLCA not only via its structural roles but also by directly regulating translational machinery through eIF4H, leading to upregulation of the metabolic enzyme ACOX2. The newly defined KRT14-eIF4H-ACOX2 axis orchestrates lipid metabolic reprogramming and cell survival, underscoring the KRT14-eIF4H interface as a promising therapeutic target for overcoming cisplatin resistance in BLCA.