Lactate-driven H3K18 lactylation promotes cisplatin resistance in bladder cancer via HNRNPF-Parkin mediated mitophagy.

Cisplatin resistance in bladder cancer (BCa) is driven by metabolic reprogramming that enhances glycolysis and lactate production. Here, we report that lactate-induced histone H3K18 lactylation (H3K18la) drives chemoresistance by activating a novel signaling axis that couples epigenetic regulation with mitochondrial quality control. Through integrative multi-omics analysis, ChIP-qPCR, and promoter reporter assays, we identified HNRNPF as a key functional effector downstream of H3K18la. Unexpectedly, HNRNPF, primarily known as an RNA-binding protein, promotes chemoresistance through a non-canonical mechanism: it directly interacts with the core mitophagy protein Parkin. Mechanistically, the RRM2 domain of HNRNPF binds the R0 domain of Parkin, facilitating Parkin's recruitment to damaged mitochondria. This interaction potentiates Parkin's E3 ubiquitin ligase activity, leading to enhanced ubiquitination of VDAC1 and robust activation of mitophagy. Collectively, our findings establish the H3K18la-HNRNPF-Parkin axis as a previously unrecognized signaling cascade that bridges epigenetic reprogramming and mitochondrial quality control in chemoresistance. Targeting this axis, particularly the HNRNPF-Parkin interaction or mitophagy activation, presents a novel therapeutic strategy to overcome cisplatin resistance in BCa.