LGALS1 promotes the malignant progression and sunitinib resistance of clear cell renal cell carcinoma by reprogramming fatty acid metabolism
- Int Immunopharmacol. 2026 Sep 15:185:117038. doi: 10.1016/j.intimp.2026.117038.
- 1. Department of Urology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200000, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai 200000, China.
- 2. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao tong University, Shanghai 200082, China.
- 3. Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address: [email protected].
- 4. Department of Urology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200000, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai 200000, China; Department of Urology, People's Hospital of Shigatse City, Tibet, China. Electronic address: [email protected].
- 5. Department of Urology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200000, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai 200000, China. Electronic address: [email protected].
- 6. Department of Urology, Chongming Branch, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200000, China; Urologic Cancer Institute, Tongji University School of Medicine, Shanghai 200000, China. Electronic address: [email protected].
Objective: Abnormal fatty acid metabolism drives clear cell renal cell carcinoma (ccRCC) occurrence, progression, and tyrosine kinase inhibitor (TKI) resistance, with unclear regulatory mechanisms. To investigate the role and molecular mechanism of fatty acid metabolism key gene LGALS1 in ccRCC malignant progression and TKI resistance.
Methods: LGALS1 was screened via TCGA-KIRC and fatty acid metabolism gene sets. Its expression, association with ccRCC prognosis, and effects on cell behaviors, fatty acid metabolism, and sunitinib resistance were evaluated using clinical samples, in vitro experiments, transcriptome Sequencing, targeted lipid metabolomics, and animal models. The correlation between LGALS1 and CPT1A on clinical outcomes was explored through a clinical cohort.
Results: High LGALS1 correlated with advanced stage, high grade, metastasis, and poor ccRCC prognosis. LGALS1 overexpression enhanced cell proliferation, migration, invasion, lipid accumulation, and sunitinib resistance by activating p38/ERK to inhibit PPARα and CPT1A. LGALS1 inhibition enhanced fatty acid oxidation, reversed resistance, and suppressed tumorigenesis.
Conclusions: LGALS1 is a prognostic marker and potential therapeutic target for intervening ccRCC metabolic abnormalities and overcoming TKI resistance.