{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:09:24Z","timestamp":1790784564992,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Cell Biology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u03b2 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\u03b2-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.<\/jats:p>","DOI":"10.64898\/2026.09.24.754142","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T08:45:18Z","timestamp":1790585118000},"source":"Crossref","is-referenced-by-count":0,"title":["SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast- like State to Drive Metabolic Disease"],"prefix":"10.64898","author":[{"given":"Karima","family":"Drareni","sequence":"first","affiliation":[{"name":"Institute for Diabetes, Obesity & Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"},{"name":"Department of Cell and Developmental Biology; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan P.","family":"Calhoun","sequence":"additional","affiliation":[{"name":"Institute for Diabetes, Obesity & Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"},{"name":"Department of Cell and Developmental Biology; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Institute for Diabetes, Obesity & Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"},{"name":"Department of Cell and Developmental Biology; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille E. 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