SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast- like State to Drive Metabolic Disease
Year: 2026
Type: preprint
Abstract: Pathogenic adipose tissue remodeling promotes metabolic disease in obesity, but the mechanisms that establish this unhealthy tissue state remain poorly understood. Here, we show that obesity drives SOX4-dependent reprogramming of mesenchymal stromal cells (MSCs) into cancer-associated fibroblast-like (CAF-like) cells that promote adipose tissue dysfunction. TGFβ signaling is elevated in obesity and activates SOX4 in mouse and human MSCs, inducing their conversion to a CAF-like state. In mice, MSC-specific SOX4 activation induces the CAF-like program and exacerbates adipose tissue inflammation and glucose intolerance, whereas Sox4 deletion attenuates inflammation and improves glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector produced by CAF-like cells. MDK inhibition in obese mice reduces adipose tissue inflammation and improves metabolic function. Together, these findings define a TGFβ-SOX4-MDK stromal signaling axis that drives pathological adipose tissue remodeling in obesity and highlight this pathway as a potential therapeutic target for improving metabolic health.
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7214632188