TOLLIP Inhibits Psoriasis Progression via Suppressing PKM2‐Mediated Glycolysis in Keratinocytes

Metabolic reprogramming toward aerobic glycolysis is increasingly recognized as a key mechanism in the pathogenesis of psoriasis, but the underlying regulatory mechanisms remain unclear. Here, we identify Toll-interacting 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)-induced psoriasis models. Mechanistically, TOLLIP interacts with the rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) via its coupling of ubiquitin to ER degradation (CUE) domain (179-274 aa), inhibits PKM2's metabolic enzyme activity and attenuates aerobic glycolysis, thereby mitigating keratinocyte hyperproliferation and inflammation. Therapeutic delivery of Tollip or Tollip (179-274 aa) via adeno-associated virus (AAV) vectors ameliorated psoriasis progression in mice. Our findings establish the TOLLIP-PKM2-glycolysis axis as a key mechanism linking metabolic reprogramming to psoriasis pathogenesis, and propose TOLLIP as a promising therapeutic target.