Itaconate Ameliorates Skin Fibrosis Through Inhibition of HIF-1α/LDHA-Driven Aerobic Glycolysis.

Authors

Linxiao Li, Xiaohui Miao, Yu Cheng, Yingying Zhuang, Wuyan Lu, Yishu Lu, Yu Jiang, Zihao Hu, Jinyi Deng, Fengting Niu, Guangpeng Liu, Lei Cui, Shuaijun Li, Jiefeng Huang

Published in

Antioxidants & redox signaling. Pages 15230864261467594. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Skin fibrosis is a hallmark of scleroderma and other fibrotic skin disorders, yet effective therapies remain limited. Immune-derived metabolites have emerged as regulators of inflammation and tissue remodeling, but whether metabolic reprogramming within dermal fibroblasts contributes to skin fibrosis remains unclear.
Human fibrotic skin samples, a bleomycin-induced mouse model, and primary dermal fibroblasts were used to investigate the role of immune-responsive gene 1 (Irg1) and its metabolic product itaconate. Transcriptomic analyses, metabolic profiling, pharmacologic modulation, and genetic perturbation were employed to define downstream signaling mechanisms.
Irg1 expression and endogenous itaconate levels were reduced in fibrotic human and murine skin. Restoration of itaconate significantly attenuated dermal thickening, collagen deposition, and fibroblast activation. Mechanistically, itaconate suppressed glycolytic reprogramming in activated fibroblasts, as evidenced by reduced glucose uptake, lactate production, and glycolytic enzyme expression. This metabolic effect was associated with inhibition of the Akt/GSK-3β pathway, destabilization of hypoxia-inducible factor 1α (HIF-1α), and subsequent downregulation of lactate dehydrogenase A (LDHA) transcription. Genetic or pharmacologic interference with HIF-1α or LDHA partially phenocopied itaconate's antifibrotic effects, supporting a functional link between itaconate signaling, fibroblast metabolism, and fibrotic progression.
This study identifies loss of Irg1-itaconate signaling as a previously unrecognized driver of fibroblast metabolic reprogramming in skin fibrosis. By revealing a fibroblast-intrinsic, metabolism-centered mechanism linking immunometabolite deficiency to extracellular matrix overproduction, these findings extend itaconate's scope beyond immune regulation and highlight metabolic targeting of fibroblasts as a promising therapeutic strategy for fibrotic skin disease. Antioxid. Redox Signal. 00, 000-000.

PMID:
42444476
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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