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Here, we identify Toll\u2010interacting protein (TOLLIP) as a critical regulator of psoriasis pathogenesis through its modulation of glycolytic metabolism. We found that TOLLIP is significantly upregulated in psoriatic lesions, and its genetic deletion in mice exacerbated disease severity in imiquimod (IMQ)\u2010induced psoriasis models. Mechanistically, TOLLIP interacts with the rate\u2010limiting glycolytic enzyme pyruvate kinase M2 (PKM2) via its coupling of ubiquitin to ER degradation (CUE) domain (179\u2013274 aa), inhibits PKM2's metabolic enzyme activity and attenuates aerobic glycolysis, thereby mitigating keratinocyte hyperproliferation and inflammation. Therapeutic delivery of Tollip or Tollip (179\u2013274 aa) via adeno\u2010associated virus (AAV) vectors ameliorated psoriasis progression in mice. Our findings establish the TOLLIP\u2010PKM2\u2010glycolysis axis as a key mechanism linking metabolic reprogramming to psoriasis pathogenesis, and propose TOLLIP as a promising therapeutic target.<\/jats:p>","DOI":"10.1002\/advs.202523390","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:47:39Z","timestamp":1785502059000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TOLLIP Inhibits Psoriasis Progression via Suppressing PKM2\u2010Mediated Glycolysis in Keratinocytes"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9606-2702","authenticated-orcid":false,"given":"Xiuhuan","family":"Jiang","sequence":"first","affiliation":[{"name":"Baoding Key Laboratory of Cancer &amp; Aging College of Life Science Hebei University Baoding 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