Evidence map›Paper›PMID 41039446›Full record

ArticleCell communication and signaling : CCS2025

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

Jiaqi Zhang, Jinjin Li, Mengting Cheng, Haiyang Zhou, Xiaochen Zhang, Hao Yan, Zhifei Xu, Bo Yang, Qiaojun He, Zizheng Gao and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Frontiers in oncology · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Jiaqi ZhangCenter 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.
Jinjin LiCenter 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.
Mengting ChengClinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, P. R. China.
Haiyang ZhouCenter 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.
Xiaochen ZhangDepartment of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, P. R. China.
Hao YanCenter 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.
Zhifei XuCenter 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.
Bo YangCenter 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.
Qiaojun HeCenter 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.
Zizheng GaoCenter 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.
Xueqin ChenDepartment 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.
Peihua LuoCenter 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.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Fatty Acid-Binding ProteinsLung Diseases, InterstitialPPAR gammaAnimalsApoptosisBiphenyl CompoundsCarnitine O-PalmitoyltransferaseHumansMiceMitochondriaPyrazolesReactive Oxygen SpeciesSignal Transduction2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acidBiphenyl CompoundsCarnitine O-PalmitoyltransferaseCPT1B protein, mouseFABP4 protein, humanFatty Acid-Binding ProteinsPPAR gammaPyrazolesReactive Oxygen Species

Identifiers

PMID41039446
PMCPMC12492827

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.