{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:16:14Z","timestamp":1787026574701,"version":"build-2736575974"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372281, 82304264"],"award-info":[{"award-number":["82372281, 82304264"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20220194"],"award-info":[{"award-number":["BK20220194"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013088","name":"Qinglan Project of Jiangsu Province of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013088","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Infection-induced orchitis, a leading cause of acquired male infertility affecting 8%\u201312% of couples globally, is driven by unresolved inflammatory responses following bacterial infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We employed uropathogenic\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (UPEC)- and lipopolysaccharide (LPS)-induced orchitis models to define the  mechanisms underlying testicular inflammation. We interrogated the cellular sources of CXCL9\/CXCL10 and assessed macrophage-driven inflammatory cell recruitment and spermatogenic disruption. Mechanistic studies were focused on lysine lactylation, STAT1 protein stability, ubiquitin\u2013proteasome\u2013mediated degradation, and the role of the E3 ubiquitin ligase TRIM21.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrate that macrophages are the predominant source of CXCL9 and CXCL10 responsible for recruiting inflammatory cells into the testis, thereby disrupting spermatogenesis. Mechanistically, the lysine lactylation in macrophages promotes STAT1-mediated CXCL9 and CXCL10 expression by inhibiting ubiquitin\u2013proteasome pathway-mediated STAT1 degradation. Specifically, K345 lactylation of the E3 ubiquitin ligase TRIM21 attenuates ubiquitin\u2013proteasome pathway-mediated STAT1 degradation in macrophages by preventing its interaction with STAT1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study provides the first evidence that non-histone lactylation (TRIM21 K345) exacerbates inflammatory orchitis and highlights TRIM21 lactylation or CXCL9\/10 as promising therapeutic targets for infection-associated male infertility.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1684836","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T06:39:43Z","timestamp":1768372783000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Macrophage TRIM21 lactylation exacerbates infection-induced orchitis through 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