HDAC11 deficiency-mediated histone lactylation drives pazopanib resistance in renal cell carcinoma by modulating the MTX1/PKM2 axis

Pazopanib resistance remains a major clinical obstacle in advanced renal cell carcinoma (RCC). This study aims to elucidate whether histone lactylation drives acquired pazopanib resistance and to identify the underlying molecular mechanisms. Pazopanib-resistant RCC cell lines (786-O-R and ACHN-R) were established through chronic dose-escalation. Metabolic profiling, Seahorse bioenergetic assays, RNA-seq, quantitative proteomics, and CUT&Tag sequencing were integrated to profile epigenetic and transcriptional alterations. Functional validations were performed via shRNA-mediated knockdown, pharmacological inhibition, and murine xenograft models. Resistant cells exhibit enhanced glycolysis and lactate accumulation, driving global histone lactylation. HDAC11 is identified as a novel histone delactylase and is significantly downregulated in resistant strains, correlating with poor patient prognosis. HDAC11 deficiency relieves H3K14la-mediated transcriptional repression at the MTX1 promoter, upregulating MTX1, which stabilizes PKM2 to sustain glycolytic flux. Disruption of the MTX1–PKM2 axis reverses resistance in vitro and in vivo, while triggering a compensatory OXPHOS shift that leads to mitochondrial structural collapse. The HDAC11/H3K14la/MTX1/PKM2 axis critically regulates metabolic plasticity and pazopanib resistance in RCC, offering a promising epigenetic–metabolic therapeutic target for overcoming treatment resistance.