Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis

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• dc.contributor.author Ruiz Blázquez, Paloma
• dc.contributor.author García-Ruiz, Carmen
• dc.contributor.author Fernández-Checa, José C.
• dc.contributor.author Moles, Anna
• dc.date.accessioned 2025-07-04T06:27:42Z
• dc.date.available 2025-07-04T06:27:42Z
• dc.date.issued 2024
• dc.description.abstract Background and objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. Methods: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. Results: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. Conclusions: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.
• dc.description.sponsorship This work was mainly funded by MCIN/AEI/10.13039/501100011033/FEDER, UE through the project grants PID2021-123652OB-I00 and RTI2018-097475-A-100 (AM); by MCIN/AEI/10.13039/501100011033 and El FSE invest in your future through the contract RYC-2016-19731 (AM); by Pfizer grant #77131383 (AM); by Ministerio de Universidades fellowships FPU19/05357 (PRB) and FPU20/01367 (MFF); by MCIN/AEI/10.13039/501100011033/FEDER, UE contract PRE2022-101676 (JCP) and CSIC contract JAEINT_23_01245 (AdCC). Additional funding sources can be found in the financial support and sponsorship section of the manuscript.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ruiz-Blázquez P, Fernández-Fernández M, Pistorio V, Martinez-Sanchez C, Costanzo M, Iruzubieta P, et al. Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis. Mol Metab. 2024 Sep;87:101989. DOI: 10.1016/j.molmet.2024.101989
• dc.identifier.doi http://dx.doi.org/10.1016/j.molmet.2024.101989
• dc.identifier.issn 2212-8778
• dc.identifier.uri http://hdl.handle.net/10230/70836
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Mol Metab. 2024 Sep;87:101989
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-123652OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-097475-A-100
• dc.rights © 2024 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Cathepsin
• dc.subject.keyword Fibrosis
• dc.subject.keyword Macrophage
• dc.subject.keyword Protease
• dc.subject.keyword Resolution
• dc.title Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion