{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:06:50Z","timestamp":1790820410081,"version":"4.1.0"},"posted":{"date-parts":[[2026,8,24]]},"group-title":"Molecular Biology","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Heart Lung and Blood Institute","award":["K08HL163406"],"award-info":[{"award-number":["K08HL163406"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]},{"award":["ES030285"],"award-info":[{"award-number":["ES030285"]}],"id":[{"id":"https:\/\/ror.org\/00j4k1h63","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ES027725"],"award-info":[{"award-number":["ES027725"]}],"id":[{"id":"https:\/\/ror.org\/00j4k1h63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The mechanisms underlying disease progression in idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases remain unclear. Increased extracellular matrix stiffness is a hallmark of fibrotic lung diseases, while monocyte-derived macrophages promote fibrosis progression. However, there is limited understanding if mechanical properties of the fibrotic microenvironment influence macrophage phenotypes and fibrogenesis. Profibrotic macrophages are resistant to apoptosis, which is modulated by enhanced mitochondrial bioenergetics. The objective of this study is to determine how lung tissue stiffness impacts macrophage phenotypes and fibrotic progression. We demonstrate that mechanoactivated macrophages exhibit apoptosis-resistance, increased expression of the antiapoptotic protein Bcl-xL, and elevated mitochondrial oxidative phosphorylation. Critically, the metabolic reprogramming observed in mechanoactivated macrophages is dependent on increased glutaminolysis. Inhibition of glutaminolysis attenuated apoptosis resistance in mechanoactivated macrophages. Moreover, inhibition of Bcl-xL\n                  <jats:italic>in vivo<\/jats:italic>\n                  protected mice against experimental pulmonary fibrosis. Lastly, mechanoactivated macrophages produce more profibrotic cytokines and promote extracellular matrix production in precision-cut lung slices. We describe a mechanism by which extracellular matrix stiffness mediates macrophage apoptosis resistance and metabolic reprogramming. Our results identify mechanoactivated apoptosis-resistant macrophages as pro-fibrotic mediators, suggesting a novel therapeutic target in IPF and related fibrotic disorders.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>GRAPHIC ABSTRACT<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"746574v5_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.23.746574","type":"posted-content","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:00:11Z","timestamp":1787608811000},"source":"Crossref","is-referenced-by-count":0,"title":["Mechanosignaling promotes macrophage apoptosis resistance in pulmonary fibrosis\n                  <i>via<\/i>\n                  metabolic reprogramming"],"prefix":"10.64898","author":[{"given":"Chao","family":"He","sequence":"first","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX"},{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neftali","family":"Garcia","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olubunmi C.","family":"Lebimoyo","sequence":"additional","affiliation":[{"name":"Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of 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