{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T12:26:50Z","timestamp":1787401610734,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671601"],"award-info":[{"award-number":["81671601"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U21A20365"],"award-info":[{"award-number":["U21A20365"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471819"],"award-info":[{"award-number":["82471819"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2408085J046"],"award-info":[{"award-number":["2408085J046"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003995","name":"Natural Science Foundation of Anhui Province","doi-asserted-by":"publisher","award":["2408085QH257"],"award-info":[{"award-number":["2408085QH257"]}],"id":[{"id":"10.13039\/501100003995","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell hyperactivation is a pivotal driver of systemic autoimmunity in systemic lupus erythematosus (SLE), yet the molecular regulators that set its activation threshold remain poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PPP2R3C expression was measured by qRT\u2010PCR and Western blotting in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from 45 SLE patients and 37 healthy controls, as well as in pristane\u2010induced lupus (PIL) mice. Jurkat cells with PPP2R3C knockdown or overexpression were generated by lentiviral transduction. Signaling mechanisms were dissected using transcriptome sequencing and calcium flux assays. In vivo, PPP2R3C was restored in PIL mice via T cell\u2010targeted Ark313 vector or systemic AAV9 delivery; disease progression was assessed at 24 and 48 weeks after pristane induction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified the protein phosphatase 2A regulatory subunit PPP2R3C as a critical and selective negative regulator of T cell receptor (TCR) signaling, which was downregulated in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells from SLE patients and pristane\u2010induced lupus (PIL) mice. Reduced PPP2R3C expression was also observed in the kidneys of both PIL mice and lupus nephritis patients. In PIL mice, this reduction was evident in podocytes, endothelial cells, and mesangial cells, indicating widespread downregulation across kidney resident cell populations. Mechanistically, PPP2R3C deficiency enhanced T cell activation, cytokine production, and calcium flux by potentiating PLC\u03b31 phosphorylation and subsequent TCR\u2010driven JNK\/c\u2010Jun signaling, whereas its overexpression produced opposing effects. To assess therapeutic potential, we restored PPP2R3C expression in PIL mice using two complementary gene delivery strategies. T cell\u2010targeted reconstitution via the Ark313 vector potently suppressed T cell activation and autoantibody production at an early stage (24 weeks), culminating in markedly attenuated proteinuria and glomerular immune complex deposition by late\u2010stage disease (48 weeks). Systemic delivery of AAV9\u2010PPP2R3C provided comprehensive therapeutic effects, ameliorating renal pathology while also normalizing immune dysregulation in both the thymus and spleen across both time points.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify PPP2R3C as an important contributor to SLE pathogenesis and support its restoration as a gene therapy approach worthy of further exploration for its ability to rebalance immunity and mitigate tissue injury in SLE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            PPP2R3C is selectively downregulated in SLE CD4\n                            <jats:sup>+<\/jats:sup>\n                            T cells and correlates with disease activity.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>It restrains the PLC\u03b31\u2010JNK axis to limit T cell hyperactivation and cytokine production.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Gene therapy restoring PPP2R3C suppresses autoimmunity and lupus nephritis in mice, and its reduction in kidney resident cells indicates a direct renoprotective effect, positioning PPP2R3C as a promising therapeutic target for SLE.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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Erlangen\u2010N\u00fcrnberg and Universit\u00e4tsklinikum Erlangen  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-033X","authenticated-orcid":false,"given":"Jinhui","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Allergy and Clinical Immunity The First Affiliated Hospital of University of Science and Technology of China  Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Nephrology The First Affiliated Hospital of University of Science and Technology of China  Hefei Anhui China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minglong","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Dermatology The First Affiliated Hospital of University of Science and Technology of China  Hefei Anhui 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