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

Oncogene volume 45, pages 650–662 (2026)Cite this article

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Abstract

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.

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Fig. 1: Histone lactylation is decreased in NSCLC/CDDP cells.
Fig. 2: Histone lactylation activated transcription of AKR1C2.
Fig. 3: The efficacy of CDDP is altered when AKR1C2 is regulated by genetic intervention in vitro and in vivo.
Fig. 4: The transcription factor CEBPB is involved in the transcriptional activation of AKR1C2.
Fig. 5: The transcriptional activation of AKR1C2 is cooperatively regulated by CEBPB and H4K12la.
Fig. 6: AKR1C2 mediated cisplatin resistance through mTOR pathway.

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All data analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82025007, 82303085 and U24A20676), the China Postdoctoral Science Foundation (2023TQ0229, 2023M742503, GZB20230491), the Natural Science Foundation of Sichuan Province (2024NSFSC1891), Innovation Group Project from Science & Technology Department of Sichuan Province (2023NSFSC1993) and the Postdoctoral Research Fund of West China Hospital, Sichuan University (2024HXBH137).

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Authors and Affiliations

  1. Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Wenjing Wang, Yimin Xiong, Qinhui Liu, Na Yang, Yining Xu, Yanping Li & Jinhan He

  2. Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Qiang He

  3. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Tianfei Fan

  4. Andrology Laboratory, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

    Yang Xiong

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Contributions

WJW and JHH conceived the study. WJW designed the experiments. WJW, QH, TFF, YX, YMX, QHL, and NY performed the experiments. WJW and QH analyzed the data. YPL, YNX, and JHH provided guidance and advice. WJW and JHH wrote and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jinhan He.

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The research presented here has been performed in accordance with the Declaration of Helsinki and has been approved by the ethics committee of Sichuan University and West China Hospital.

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Wang, W., He, Q., Fan, T. et al. An H4K12la/CEBPB-AKR1C2 signaling axis modulates the mTOR pathway to regulate cisplatin resistance in lung cancer. Oncogene 45, 650–662 (2026). https://doi.org/10.1038/s41388-025-03669-6

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