AI-assisted image-based screening identifies TFEB agonists that restore adipose angiogenesis and reduce adipose fibrosis

Adipose tissue expansion in obesity frequently outpaces vascularization, triggering hypoxia, fibrosis, and metabolic dysfunction. The molecular mechanisms coordinating adaptive angiogenesis during this expansion remain poorly understood. Here, we demonstrate that myeloid deletion of Transcription Factor EB ( Tfeb ) in high-fat diet-fed mice exacerbates epididymal white adipose tissue (eWAT) dysfunction, manifesting as profound hypoxia, fibrosis, and systemic insulin resistance. Mechanistically, single-cell RNA sequencing and chromatin immunoprecipitation assays reveal a novel TFEB-VEGFA axis: TFEB directly activates Vegfa transcription in macrophages, and its absence impairs angiogenic compensation under hypoxic stress. To translate these findings, we established an AI-driven, high-content screening platform to quantify TFEB nuclear translocation. We identified and validated Tetrandrine and Pacritinib as potent TFEB agonists. Notably, Tetrandrine acts via an mTOR-independent mechanism. Pharmacological activation of TFEB with these compounds restored adipose angiogenesis, resolved fibrosis, and improved insulin sensitivity in obese mice. These findings establish macrophage TFEB as a critical regulator of healthy adipose remodeling and validate the TFEB-VEGFA axis as a therapeutic target for metabolic diseases.