2. Academic Validation
  3. TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition

TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition

  • EMBO J. 2026 Apr;45(7):2182-2209. doi: 10.1038/s44318-026-00712-4.
Eva-Maria Weiden # 1,  Zala Serianz # 1,  Yvonne Klingl # 2,  Simone Jörs # 3,  Dawid Jaślan 1,  Marco Keller 4,  Sandra Prat Castro 1,  Mane Mkhitaryan 1,  Aicha Jeridi 5,  Daria Briukhovetska 6,  Barbara Spix 1,  Anna Scotto Rosato 1,  Ahmed Agami 5,  Herbert B Schiller 5,  Suhasini Rajan 1,  Johann Schredelseker 1,  Giorgio Fois 7,  Manfred Frick 7,  Sebastian Kobold 6 8 9,  Margarethe Klein 10,  Fabian Geisler 3,  Jorge Garcia-Fortanet 11,  Leon O Murphy 11,  Franz Bracher 4,  Christian Wahl-Schott 12,  Thomas Gudermann 1 5,  Alexander Dietrich 1 5,  Martin Biel 13,  Ali Önder Yildirim 14,  Christian Grimm 15 16 17
Affiliations

Affiliations

  • 1 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany.
  • 2 Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Munich/Frankfurt, Germany.
  • 3 TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, Munich, Germany.
  • 4 Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
  • 5 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
  • 6 Division of Clinical Pharmacology, Department of Medicine IV, University Hospital Munich, Munich, Germany.
  • 7 Department of Physiology, University of Ulm, Ulm, Germany.
  • 8 German Cancer Consortium (DKTK), partner site Munich, Munich, Germany.
  • 9 German Center for Lung Research (DZL), partner site Munich, Munich, Germany.
  • 10 Institute for Neurophysiology, Hannover Medical School, Hannover, Germany.
  • 11 Casma Therapeutics, 201 Brookline Ave, Boston, MA, 02215, USA.
  • 12 Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Munich, Germany.
  • 13 Department of Pharmacy, Ludwig-Maximilians-University, Munich, Germany. [email protected].
  • 14 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany. [email protected].
  • 15 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany. [email protected].
  • 16 Immunology, Infection and Pandemic Research IIP, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Munich/Frankfurt, Germany. [email protected].
  • 17 Department of Pharmacology, Faculty of Medicine, University of Oxford, Oxford, UK. [email protected].
  • # Contributed equally.
PMID: 41714729 DOI: 10.1038/s44318-026-00712-4
Abstract

In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as Collagen and elastin. ECM proteins are degraded predominantly by Matrix Metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate Collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular Collagen and elastin accumulation.

Keywords

Mcoln1; Pulmonary Fibrosis; TRPML; TRPML1; TRPML3.

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