{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:01Z","timestamp":1787199961395,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      have recently been identified in patients with palmoplantar keratoderma (PPK). Clinically, SERPINA12-associated PPK shares substantial overlap with Nagashima-type palmoplantar keratoderma (NPPK) caused by SERPINB7 deficiency, although inflammatory manifestations appear to be more prominent in SERPINA12-associated disease. The molecular basis underlying these similarities and differences remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Virtual knockout analyses of\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      and\n                      <jats:italic>SERPINB7<\/jats:italic>\n                      were performed using the scTenifoldKnk framework. Functional enrichment analyses, including GO, KEGG, and GSEA, were conducted to characterize perturbed biological pathways. Correlation analyses were performed using extracellular matrix (ECM)- and inflammation-related gene signatures. In addition,\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      was overexpressed in TNF-\u03b1-stimulated HaCaT keratinocytes to evaluate its effects on inflammatory cytokine expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      and\n                      <jats:italic>SERPINB7<\/jats:italic>\n                      were associated with ECM-related biological processes and pathways, suggesting a potential shared role in extracellular matrix homeostasis. However,\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      deficiency preferentially perturbed immune- and inflammation-related pathways, including Toll-like receptor signaling, interleukin signaling, and leukocyte activation. Consistently,\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      overexpression significantly reduced TNF-\u03b1, IL-8, and IL-1\u03b2 expression in TNF-\u03b1-stimulated HaCaT cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      and\n                      <jats:italic>SERPINB7<\/jats:italic>\n                      are associated with extracellular matrix-associated functions that may account for their similar keratoderma phenotypes. In contrast,\n                      <jats:italic>SERPINA12<\/jats:italic>\n                      additionally may exerts anti-inflammatory effects, providing a potential molecular explanation for the enhanced inflammatory manifestations observed in SERPINA12-associated PPK.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1920631","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:15:47Z","timestamp":1787199347000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated bioinformatics analysis reveals convergent molecular signatures associated with SERPINB7 and SERPINA12 deficiency"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhenzhen","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Dermatology, Fuzhou First General Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixiao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charit\u00e9 - Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunqian","family":"Zhuo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fuzhou First General Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Beijing Pinsu Medical Aesthetic Clinic","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Fuzhou First General Hospital","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjian","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, Charit\u00e9 - Universit\u00e4tsmedizin Berlin","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1812302","DOI":"10.3389\/fimmu.2026.1812302","article-title":"Serpina12 in skin: molecular mechanisms and roles in adipocytes, psoriasis, and palmoplantar keratoderma","volume":"17","author":"Xiao","year":"2026","journal-title":"Front Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1111\/jdv.19498","article-title":"A novel Serpina12 variant and first European patients with diffuse palmoplantar keratoderma","volume":"38","author":"Brandt","year":"2024","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e146","DOI":"10.1111\/1346-8138.13880","article-title":"Novel nonsense mutation in Serpinb7 and the treatment of foot odor in a patient with Nagashima-type palmoplantar keratosis","volume":"44","author":"Katsuno","year":"2017","journal-title":"J Dermatol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1624512","DOI":"10.3389\/fgene.2025.1624512","article-title":"The roles of serine protease inhibitors in dermatoses","volume":"16","author":"Xiao","year":"2025","journal-title":"Front Genet"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"707411","DOI":"10.3389\/fgene.2021.707411","article-title":"Identification of a rare case with Nagashima-type palmoplantar keratoderma and 18q deletion syndrome via exome sequencing and low-coverage whole-genome sequencing","volume":"12","author":"Li","year":"2021","journal-title":"Front Genet"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1111\/1346-8138.16310","article-title":"Two novel mutations of Serpinb7 in eight cases of Nagashima-type palmoplantar keratosis in the Chinese population","volume":"49","author":"Xiao","year":"2022","journal-title":"J Dermatol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1111\/jdv.14902","article-title":"Hereditary palmoplantar keratodermas. 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