A natural compound derivative targeting HADHA disrupts mitochondrial homeostasis and suppresses renal cell carcinoma.

Abstract

Metastatic renal cell carcinoma (RCC) remains a lethal malignancy, and therapeutic resistance to current targeted and immune-based therapies highlights the need for new treatment strategies. Here, we identify C18-epi-brasilibactin A (CBA) as a selective inhibitor of RCC. High-throughput screening of a compound library derived from natural-products revealed that CBA potently suppresses RCC cell proliferation while sparing normal renal epithelial and liver cells. Mechanistically, CBA induces cell-cycle arrest, apoptosis, and DNA damage. Transcriptomic and functional analyses showed that CBA disrupts mitochondrial homeostasis by increasing mitochondrial mass and reactive oxygen species, indicating metabolic stress. Using proteomic approaches, we identified hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a key enzyme in mitochondrial fatty acid β-oxidation, as a key functional mediator of CBA. Genetic depletion of HADHA phenocopied CBA effects, inducing ROS accumulation, DNA damage response, apoptosis, and growth inhibition in RCC cells. CBA treatment significantly suppressed RCC xenograft growth without systemic toxicity. Consistently, HADHA knockdown inhibited tumor progression, whereas HADHA overexpression enhanced tumor growth, supporting a tumor-supportive role for HADHA in RCC. Together, our findings identify HADHA-dependent mitochondrial metabolism as a functional vulnerability in RCC and establish CBA as a candidate therapeutic agent for targeting metabolic dependencies in metastatic renal cell carcinoma.