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Here, gemcitabine\u2010resistant pancreatic cancer cell lines and patient\u2010derived xenograft (PDX) models are established, followed by high\u2010throughput 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\u2010omics analysis reveals that histone H3 lysine18 lactylation (H3K18la) drives HNRNPC overexpression. HNRNPC stabilizes TNF receptor\u2010associated factor 6 (TRAF6) transcripts in an N6\u2010methyladenosine(m6A) \u2010dependent 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\u2010reinforcing histone lactylation\u2010HNRNPC 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\u2010driven positive feedback loop sustaining chemoresistance through HNRNPC\u2010mediated autophagy activation, but also develop the potential of 673A as a promising clinical candidate for overcoming gemcitabine resistance in PDAC treatment.<\/jats:p>","DOI":"10.1002\/advs.202510483","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T03:58:47Z","timestamp":1764302327000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Positive Feedback Loop of Histone Lactylation\u2010Driven HNRNPC Promotes Autophagy to Confer Pancreatic Ductal Adenocarcinoma Gemcitabine Resistance"],"prefix":"10.1002","volume":"13","author":[{"given":"Xi\u2010Tai","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pancreato\u2010Biliary Surgery The First Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou 510080 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