2. Academic Validation
  3. Off-target engagement of sotorasib with PPARγ via FABP4: a novel mechanism driving interstitial lung disease

Off-target engagement of sotorasib with PPARγ via FABP4: a novel mechanism driving interstitial lung disease

  • Cell Commun Signal. 2025 Oct 2;23(1):416. doi: 10.1186/s12964-025-02425-3.
Jiaqi Zhang 1,  Jinjin Li 1,  Mengting Cheng 2,  Haiyang Zhou 1,  Xiaochen Zhang 3,  Hao Yan 1,  Zhifei Xu 1,  Bo Yang 1 4 5,  Qiaojun He 1 5,  Zizheng Gao 6,  Xueqin Chen 7,  Peihua Luo 8 9
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Zijingang Campus, Hangzhou, 310058, Zhejiang, P. R. China.
  • 2 Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, P. R. China.
  • 3 Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, P. R. China.
  • 4 School of Medicine, Hangzhou City University, Hangzhou, 310015, P. R. China.
  • 5 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, Zhejiang, P. R. China.
  • 6 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Zijingang Campus, Hangzhou, 310058, Zhejiang, P. R. China. zizhenggao@zju.edu.cn.
  • 7 Department of Thoracic Oncology, School of Medicine, Hangzhou Cancer Hospital, Affiliated Hangzhou First People's Hospital, Westlake University, Hangzhou, 310006, Zhejiang, P. R. China. chenxueqin@hospital.westlake.edu.cn.
  • 8 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Zijingang Campus, Hangzhou, 310058, Zhejiang, P. R. China. peihualuo@zju.edu.cn.
  • 9 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 310018, Zhejiang, P. R. China. peihualuo@zju.edu.cn.
PMID: 41039446 DOI: 10.1186/s12964-025-02425-3
Abstract

Sotorasib, the first FDA-approved KRAS G12C inhibitor, has demonstrated remarkable clinical efficacy in non-small cell lung Cancer (NSCLC). However, its clinical utility is hampered by life-threatening interstitial lung disease (ILD), whose molecular basis remains unknown. Through the integration of transcriptomic and metabolomic analyses, we revealed that sotorasib activates PPAR-γ signaling, upregulating fatty acid oxidation (FAO) via its downstream effector CPT1B. This metabolic shift triggered mitochondrial ROS overproduction, which drives alveolar epithelial Apoptosis and fibrosis in vivo and in vitro. Mechanistically, sotorasib directly binds to PPAR-γ via Thr325, facilitated by FABP4-mediated nuclear translocation, amplifying its transcriptional activity via a feedforward loop. Pharmacological inhibition of FABP4 attenuated PPAR-γ activation, mitigated ROS-driven Apoptosis, and rescued pulmonary fibrosis in mice. Taken together, these findings identify the FABP4-PPARγ-CPT1b axis as a novel off-target mechanism of sotorasib-induced lung toxicity and propose FABP4 inhibition as a promising therapeutic target to enhance its clinical safety.

Graphical Abstract:

Supplementary Information: The online version contains supplementary material available at 10.1186/s12964-025-02425-3.

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