SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast-like State to Drive Metabolic Disease

Drareni, K.; Calhoun, R.; Cheng, L.; Piquet, C. E. M.; Liu, L.; Traynor, S.; Tan, J. M.; Angelozzi, M.; Merric, D. M.; Lefebvre, V.; Seale, P.

doi:10.64898/2026.09.24.754142

bioRxiv · 10.64898/2026.09.24.754142

SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast-like State to Drive Metabolic Disease

Drareni, K.·Calhoun, R.·Cheng, L.·Piquet, C. E. M.·Liu, L.·Traynor, S.·Tan, J. M.·Angelozzi, M.·Merric, D. M.·Lefebvre, V.·Seale, P.

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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. TGF{beta} 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 TGF{beta}-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.

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Drareni, K., Calhoun, R., Cheng, L., Piquet, C. E. M., Liu, L., Traynor, S., Tan, J. M., Angelozzi, M., Merric, D. M., Lefebvre, V., Seale, P.. 2026-09-28. SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast-like State to Drive Metabolic Disease. https://doi.org/10.64898/2026.09.24.754142

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