{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:05:07Z","timestamp":1780988707489,"version":"3.54.1"},"reference-count":23,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":158,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis is a life\u2010threatening condition marked by excessive inflammation and immune dysregulation. Macrophages are central to this process. Podoplanin (PDPN), a transmembrane glycoprotein, is upregulated in inflammatory macrophages, but its role in sepsis remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The aim of this study is to investigate the role of PDPN and the therapeutic potential of its monoclonal antibody SZ168 in LPS\u2010induced macrophages and to extend these observations with supplementary in vivo and preliminary clinical validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RAW264.7 macrophages were stimulated with LPS and treated with SZ168. PDPN expression and the effects of SZ168 on cytokine secretion, polarization, apoptosis, and ERK signaling were assessed by proteomics, qPCR, Western blotting, ELISA, and flow cytometry. siRNA\u2010mediated PDPN knockdown was used to validate pathway dependence. During revision, additional Western blot validation of MEK, p90RSK, and c\u2010Fos; supplementary in vivo experiments in a mouse sepsis model; and a preliminary clinical cohort analysis were incorporated to strengthen mechanistic and translational relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LPS stimulation significantly upregulated PDPN expression at both mRNA and protein levels in macrophages. SZ168 treatment reduced LPS\u2010induced secretion of IL\u20106, TNF\u2010\n                      <jats:italic>\u03b1<\/jats:italic>\n                      , and IL\u20101\n                      <jats:italic>\u03b2<\/jats:italic>\n                      ; promoted anti\u2010inflammatory polarization; and attenuated apoptosis. Revision\u2010stage Western blot analyses further showed coordinated recovery of MEK, p90RSK, c\u2010Fos, and p\u2010ERK together with suppression of SERPINE1 after SZ168 treatment, especially in PDPN\u2010knockdown cells. Supplementary in vivo experiments showed lower BUN, creatinine, inflammatory cytokines, and lung injury after SZ168 treatment. In a preliminary clinical cohort, serum PDPN levels were higher in patients with sepsis than in controls (23.81 \u00b1 17.64 vs. 3.53 \u00b1 0.58,\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The PDPN monoclonal antibody SZ168 attenuates inflammatory responses, promotes anti\u2010inflammatory macrophage polarization, and inhibits apoptosis through modulation of the ERK signaling pathway in LPS\u2010induced macrophages. The supplementary in vivo and preliminary human data added during revision further support the translational relevance of PDPN as a therapeutic target in sepsis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/3791421","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T06:19:56Z","timestamp":1780985996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Podoplanin Antibody SZ168 Alleviates Sepsis Inflammation and Macrophage Dysregulation via ERK Signaling"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0855-1087","authenticated-orcid":false,"given":"Hongbin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Heng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-5693","authenticated-orcid":false,"given":"Shiqi","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6960-9370","authenticated-orcid":false,"given":"Yiming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-024-07694-z"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i1585"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.10.029"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1209438"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes11030323"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1101918"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06002-x"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20220531"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00541-3"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.173090"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001388"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.07.015"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.693974"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02402-6"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.07.053"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.14643"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2022.103965"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-32-9717-3_3"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154658"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2017.11.031"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.71595"},{"key":"e_1_2_8_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bj.2023.100631"}],"container-title":["Human 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