Post-transcriptional regulation via alternative polyadenylation and piRNA shapes macrophage responses in psoriasis.

BACKGROUND: 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. METHODS: 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-γ-polarized THP-1 macrophages following TDRKH knockdown. RESULTS: Integrating multi-tissue genetic validations across GTEx, eQTLGen, and FinnGen datasets, we identified TDRKH as a robust psoriasis susceptibility gene (PPH4 > 0.92). TDRKH exhibited significant APA alterations in psoriatic PBMCs, with preferential usage of the distal polyadenylation site leading to 3'UTR lengthening (PDI = -0.574). Reporter gene assays confirmed that the long 3'UTR isoform conferred approximately 3-fold greater mRNA stability (t½ = 6.9 h vs. 2.3 h). 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-γ-polarized 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-piRNA axis in macrophage inflammatory activation. CONCLUSIONS: 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.