ArticleCommunications biology2025
Lactate orchestrates the TGFβ pathway and ferroptosis nexus in organ fibrosis via USP2 lactylation.
Article in Communications biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Breaking the cycle of fibrosis: Ferroptosis as a therapeutic target (Review).International journal of molecular medicine · 2026Review
- Lactate-Mediated Lysine Lactylation in Renal Fibrosis: Current Progress and Challenges.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Lactate-dependent regulation of ferroptosis: redox homeostasis, lactylation, and translational perspectives.Apoptosis : an international journal on programmed cell death · 2026Review
- Lysine l-Lactylation: Bridging Metabolism, Chromatin and Disease.Cell proliferation · 2026Review
- Glycolytic lactylation modulates cell death decisions in diabetic kidney disease: Metabolic‑epigenetic interplay between ferroptosis and autophagy in fibrotic remodeling (Review).International journal of molecular medicine · 2026Review
- Lactylation-regulated ferroptosis: mechanisms, disease associations, and therapeutic strategies.Archives of pharmacal research · 2026Review
- Pheophytin a from Microcystis aeruginosa exerts antidiabetic activity in streptozotocin-induced diabetes in rat model.AMB Express · 2026Article
- Lactylation in tissue fibrosis: epigenetic mechanisms, metabolic crosstalk, and therapeutic opportunities.Journal of translational medicine · 2026Review
- The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets.International journal of molecular sciences · 2026Review
- Energy-sensing molecule RORγ regulates cholesterol metabolism and immune signaling in diabetic kidney disease and aging.Nature communications · 2026Article
- Emerging Role of Sirtuins-Mediated Ferroptosis in Hepatocellular Carcinoma Progression: Mechanisms and Therapeutic Perspectives.Journal of hepatocellular carcinoma · 2026Review
- Research progress on protein lactylation in female reproductive disease: molecular mechanisms, functions, and therapeutic implications.Frontiers in pharmacology · 2026Review
- Lactylation in sepsis-associated acute kidney injury: regulatory mechanisms and therapeutic prospects.Frontiers in molecular biosciences · 2026Review
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Authors and funding
10 authors.
Funding
Abstract
TGFβ1 and ferroptosis are key drivers of organ fibrosis, but their crosstalk remains unclear. This study aims to identify the key regulatory ubiquitin-specific protease (USP) in organ fibrosis, TGFβ signaling transduction, and ferroptosis. Here, we show that global or renal tubule-specific deletion of Usp2 ameliorates kidney fibrosis in UUO models of male mice, while kidney tubule-specific Usp2 overexpression exacerbates fibrosis and reverses the protective effect conferred by global Usp2 deletion. Mechanistically, USP2 deubiquitinates TXNDC5, an ER protein that stabilizes TGFβR1 to activate TGFβ signaling. USP2 also deubiquitinates the transferrin receptor (TFRC), enhancing TFRC's role in promoting ferroptosis. TGFβ1 lactylates USP2 at Lys447 to facilitate deubiquitination of TXNDC5 and TFRC, whereas SIRT2 delactylates USP2 at Lys447 to suppress its activity. Notably, the USP2 inhibitor ML364 alleviates fibrosis in male mouse models of kidney, liver, and lung mouse models. Our findings establish USP2 as a key regulator of the TGFβ pathway and ferroptosis, highlighting its potential as a therapeutic target for fibrosis.
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