{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T07:01:33Z","timestamp":1788850893389,"version":"build-2803163510"},"posted":{"date-parts":[[2025,12,15]]},"group-title":"Cell Biology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Marshall University Institute Fund"},{"award":["R15HL145573"],"award-info":[{"award-number":["R15HL145573"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R01HL177493-01A1"],"award-info":[{"award-number":["1R01HL177493-01A1"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54GM104942"],"award-info":[{"award-number":["U54GM104942"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P20GM103434"],"award-info":[{"award-number":["P20GM103434"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Rationale and Objectives<\/jats:title>\n                  <jats:p>COVID-19 survivors exhibit increased interstitial lung fibrosis, a known risk factor for lung cancer. We investigated whether SARS-CoV-2 Spike protein (SP)\u2013induced lung injury and elevated thymidine phosphorylase (TYMP) promote lung tumorigenesis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    A TriNetX retrospective cohort analysis was combined with mechanistic studies in K18-hACE2\n                    <jats:sup>TG<\/jats:sup>\n                    and K18-hACE2\n                    <jats:sup>TG<\/jats:sup>\n                    \/\n                    <jats:italic>\n                      Tymp\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Mice received intratracheal SP or control lysate followed by a urethane-induced lung cancer protocol. Lung injury, inflammation, thrombosis, fibrosis, STAT3 activation, cytokine profiles, and tumor burden were assessed. In vitro assays evaluated SP- and RBD-induced ACE2 processing.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Propensity score\u2013matched TriNetX cohorts demonstrated an increased lung cancer risk after COVID-19, particularly among current smokers (n = 166,807; RR 1.22; HR 1.50; P &lt; .001). In mice, SP induced acute lung injury, neutrophil infiltration, and microthrombi, which were reduced in TYMP-deficient mice. SP markedly increased lung tumor incidence and aggressiveness, whereas TYMP deficiency reduced tumor formation from 50% to 18% of lung lobes. SP-induced STAT3 upregulation and collagen deposition were significantly attenuated in K18-hACE2\n                    <jats:sup>TG<\/jats:sup>\n                    \/\n                    <jats:italic>\n                      Tymp\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Cytokine profiling revealed a tumor-promoting, myeloid-dominant inflammatory milieu in K18-hACE2\n                    <jats:sup>TG<\/jats:sup>\n                    mice, in contrast to a T cell\u2013inflamed, anti-tumor profile in K18-hACE2\n                    <jats:sup>TG<\/jats:sup>\n                    \/\n                    <jats:italic>\n                      Tymp\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. SP and RBD altered ACE2 processing, generating lower\u2013molecular-weight fragments consistent with enhanced turnover.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>SARS-CoV-2 SP drives lung injury, fibrosis, and tumorigenesis through a TYMP-dependent mechanism involving STAT3 signaling and inflammatory microenvironment remodeling. COVID-19 significantly increases lung cancer risk, especially in current smokers.<\/jats:p>\n                  <jats:p>TYMP represents a potential therapeutic target to mitigate long-term pulmonary consequences of COVID-19.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.14.694192","type":"posted-content","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T02:50:11Z","timestamp":1765853411000},"source":"Crossref","is-referenced-by-count":1,"title":["Thymidine Phosphorylase Drives SARS-CoV-2 Spike Protein-Induced Lung Tumorigenesis"],"prefix":"10.64898","author":[{"given":"Cayleigh","family":"Wallace","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0656-905X","authenticated-orcid":false,"given":"Alex","family":"Gileles-Hillel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gozal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7973-6242","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025121721051902000_2025.12.14.694192v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"2025121721051902000_2025.12.14.694192v1.2","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1111\/imr.12977","article-title":"COVID-19 and pulmonary fibrosis: A potential role for lung epithelial cells and fibroblasts","volume":"302","year":"2021","journal-title":"Immunol Rev"},{"key":"2025121721051902000_2025.12.14.694192v1.3","doi-asserted-by":"crossref","unstructured":"Zhao YM , Shang YM , Song WB , Li QQ , Xie H , Xu QF , Jia JL , Li LM , Mao HL , Zhou XM , Luo H , Gao YF , Xu AG . 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