Positive Feedback Loop of Histone Lactylation‐Driven HNRNPC Promotes Autophagy to Confer Pancreatic Ductal Adenocarcinoma Gemcitabine Resistance

Gemcitabine resistance remains a primary determinant of poor survival outcomes in pancreatic ductal adenocarcinoma (PDAC) patients, underscoring the urgent need to elucidate its molecular mechanisms and develop effective countermeasures. Here, gemcitabine-resistant pancreatic cancer cell lines and patient-derived xenograft (PDX) models are established, followed by high-throughput sequencing, which identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a significantly upregulated factor in chemoresistant tumors. Silencing of HNRNPC expression substantially restores sensitivity to gemcitabine treatment in vitro and vivo. Mechanistically, multi-omics analysis reveals that histone H3 lysine18 lactylation (H3K18la) drives HNRNPC overexpression. HNRNPC stabilizes TNF receptor-associated factor 6 (TRAF6) transcripts in an N6-methyladenosine(m6A) -dependent manner, thereby activating autophagy to mediate gemcitabine resistance. Concurrently, HNRNPC orchestrates a metabolic reprogramming cascade by similarly stabilizing aldehyde dehydrogenase 1 family member A3 (ALDH1A3) mRNA, which enhances glycolysis and H3K18la levels, establishing a self-reinforcing histone lactylation-HNRNPC positive feedback loop. Notably, pharmacological inhibition of ALDH1A3 using 673A effectively disrupted this regulatory circuit and exerts a synergistic effect with gemcitabine in PDX. These findings not only delineate a histone lactylation-driven positive feedback loop sustaining chemoresistance through HNRNPC-mediated autophagy activation, but also develop the potential of 673A as a promising clinical candidate for overcoming gemcitabine resistance in PDAC treatment.