An H4K12la/CEBPB-AKR1C2 signaling axis modulates the mTOR pathway to regulate cisplatin resistance in lung cancer.

Histone lactylation, a recently discovered epigenetic modification, has been shown to play a critical role in regulating gene expression and cellular functions. However, its involvement in cisplatin (CDDP) resistance in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we demonstrated that histone lactylation is closely associated with CDDP resistance and correlates with poor prognosis of NSCLC. Mechanistically, H4K12la (histone e 4 lysine 12 lactylation) levels and CEBPB (CCAAT/enhancer-binding protein beta) had a cooperative effect on the regulation of AKR1C2 (Aldo-Keto reductase 1C2). Furthermore, AKR1C2 knockdown activates the mTOR oncogenic signaling pathway. Importantly, genetic manipulation of AKR1C2 or the combination of CDDP with an mTOR inhibitor effectively reverse CDDP resistance in NSCLC/CDDP cells. These findings highlighted the potential of AKR1C2 as a predictive biomarker for patient response to CDDP therapy. Additionally, our study established a novel link between histone lactylation and CDDP resistance, providing new insights into the epigenetic regulation in NSCLC.