Soulangianolide A targets FAM120A to disrupt SREBP1-driven lipid metabolic reprogramming and suppress clear cell renal cell carcinoma

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is characterized by extensive lipid metabolic reprogramming that drives tumor progression and therapeutic resistance. Although sterol regulatory element-binding protein 1 (SREBP1) is a central regulator of lipogenesis in ccRCC, the upstream mechanisms governing its activation remain poorly defined. Here, we investigated the role of FAM120A in SREBP1-dependent lipid metabolism and evaluated the therapeutic potential of the natural product Soulangianolide A (SA). METHODS: Stable knockdown of SREBP1 or FAM120A was established in ccRCC cells to assess lipid metabolism and malignant phenotypes. The antitumor activity and molecular mechanism of SA were investigated using integrated lipidomic, transcriptomic, proteomic, biochemical, and xenograft analyses, together with molecular docking, pull-down assays, surface plasmon resonance, and cellular thermal shift assays. RESULTS: Genetic depletion of SREBP1 suppressed lipogenic gene expression, intracellular lipid accumulation, and malignant phenotypes in ccRCC cells. FAM120A promoted SREBP1 nuclear accumulation and transcriptional activity, whereas SA inhibited SREBP1 signaling, reduced lipid storage, and induced apoptosis. Multi-omics analyses revealed extensive metabolic remodeling characterized by depletion of triglycerides and membrane lipids, accompanied by accumulation of ceramides and acylcarnitines, indicative of a lipotoxic state. Mechanistically, SA directly bound FAM120A at Cys531, disrupted the FAM120A-SREBP1 complex, impaired SREBP1 nuclear activity, and consequently attenuated lipid-dependent PPARγ signaling. In xenograft models, SA significantly suppressed tumor growth, reduced intratumoral lipid accumulation, inhibited SREBP1-driven lipogenic signaling, and potentiated the antitumor efficacy of MK-6482. CONCLUSIONS: Our findings identify the FAM120A-SREBP1-PPARγ axis as a critical driver of lipid metabolic reprogramming in ccRCC, establish FAM120A as a direct molecular target of SA, and demonstrate that pharmacological disruption of this pathway effectively suppresses tumor growth. These findings provide a mechanistic rationale for targeting lipid metabolic reprogramming in ccRCC and support SA as a promising metabolism-targeted therapeutic strategy.