{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:03:30Z","timestamp":1784783010772,"version":"3.55.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Post-transcriptional regulatory mechanisms underlying autoimmune diseases remain poorly understood. Here, we employed integrated multi-omics approaches to systematically dissect the role of alternative polyadenylation (APA) and piRNA-mediated regulation in psoriasis pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed transcriptome-wide association studies (TWAS) combined with Mendelian randomization to identify causal susceptibility genes. Long-read sequencing was used to characterize APA landscapes in 15 healthy controls and 10 psoriasis patients. Single-cell RNA sequencing was performed on lesional tissues from 4 patients to define cell-specific expression patterns. Small RNA sequencing was conducted to profile piRNA regulation in LPS + IFN-\u03b3\u2013polarized THP-1 macrophages following TDRKH knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Integrating multi-tissue genetic validations across GTEx, eQTLGen, and FinnGen datasets, we identified TDRKH as a robust psoriasis susceptibility gene (PPH4 &amp;gt; 0.92). TDRKH exhibited significant APA alterations in psoriatic PBMCs, with preferential usage of the distal polyadenylation site leading to 3\u2032UTR lengthening (PDI = \u22120.574). Reporter gene assays confirmed that the long 3\u2032UTR isoform conferred approximately 3-fold greater mRNA stability (t\u00bd = 6.9\u00a0h vs. 2.3\u00a0h). Single-cell RNA sequencing of psoriatic skin (4 patients, 17,734 cells) identified 17 cell types and 10 macrophage\/myeloid subpopulations using marker gene-based annotation with TDRKH excluded from feature selection. TDRKH expression was highest in IL-23-producing macrophages (IL23A+IL1B+), which were selectively enriched in lesional tissue. TDRKH knockdown in LPS + IFN-\u03b3\u2013polarized THP-1 macrophages altered piRNA expression profiles, reduced pro-inflammatory surface markers (CD80, CD86, HLA-DR), and attenuated IL6 and IL1B expression, supporting a functional role of the TDRKH\u2013piRNA axis in macrophage inflammatory activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal a previously unrecognized post-transcriptional regulatory network involving APA and piRNA that governs macrophage-driven inflammation. The discovery of the TDRKH-piRNA axis provides novel mechanistic insights into psoriasis and establishes a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1760348","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:28:00Z","timestamp":1784780880000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Post-transcriptional regulation via alternative polyadenylation and piRNA shapes macrophage responses in psoriasis"],"prefix":"10.3389","volume":"17","author":[{"given":"Benfan","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Dermatology, Linyi People\u2019s Hospital","place":["Linyi, China"]},{"name":"Department of Dermatology, General Hospital of Fushun Mining Bureau of Liaoning Health Industry Group","place":["Fushun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiwang","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Femoral Head, Linyi People\u2019s Hospital","place":["Linyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leihong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Linyi People\u2019s Hospital","place":["Linyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongshan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Linyi People\u2019s Hospital","place":["Linyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Linyi People\u2019s Hospital","place":["Linyi, 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