Authors
Lin Huang, Ling Cheng, Jin He, Rui Zhang, Xia Li, Qiurong Xia
Published in
Frontiers in cell and developmental biology. Volume 14. Pages 1951682. Epub Oct 16, 2026.
Abstract
Adhesive capsulitis (AC) is a fibroinflammatory disorder characterized by painful shoulder restriction and progressive capsular fibrosis. Whether regulated cell-death (RCD) programs are consistently altered across independent transcriptomic cohorts remains uncertain.
We reanalyzed three public bulk RNA-seq cohorts. GSE140731 was the discovery cohort (22 AC and 26 shoulder-instability surgical controls), and GSE190023 and GSE238053 were independent validation cohorts. Differential expression was estimated from filtered raw counts with PyDESeq2, with age/sex adjustment in GSE140731. Curated pyroptosis, ferroptosis, and necroptosis gene sets; immune marker-gene scores; pathway enrichment; STRING network structure; cross-cohort concordance; an exploratory three-gene classifier; and qPCR validation of four selected genes in TGF-β1-stimulated SW982 cells were evaluated.
The adjusted discovery analysis identified 439 upregulated and 113 downregulated genes at FDR < 0.05. ECM-receptor interaction was strongly positively enriched (NES = 2.299, q = 0.001), making extracellular-matrix remodeling the clearest pathway-level signal. RCD findings were mixed: pyroptosis was not different (delta = -0.105, q = 0.708), ferroptosis was lower but borderline after FDR correction (delta = -0.426, q = 0.056), and necroptosis was lower (delta = -0.320, q = 0.035); the core necroptosis gene set was also negatively enriched (NES = -1.673, q = 0.038). Six immune marker scores were FDR-significant in discovery, but none replicated at cohort-wise FDR significance in the validation cohorts. Cross-cohort gene-effect concordance was heterogeneous (Spearman rho = -0.047 for GSE190023 and 0.383 for GSE238053). The COL11A1-SPON2-PITPNC1 classifier achieved a pooled out-of-fold AUC of 0.820 (95% CI, 0.684-0.930) in GSE140731; external-cohort AUCs ranged from 0.750 to 0.812 with wide confidence intervals, and non-nested feature selection precluded claims of clinical utility. qPCR showed higher COL11A1 and SPON2 and lower PLA2G4A expression after TGF-β1 stimulation, whereas PITPNC1 did not differ significantly, providing model-specific support without establishing causal or clinical validity.
Across the three cohorts, ECM remodeling was the most reproducible feature of AC, whereas RCD- and immune-related signals were cohort-dependent and did not support uniform activation of pyroptosis, ferroptosis, or necroptosis. The classifier and RCD signatures remain hypothesis-generating. The SW982 qPCR results provide model-specific experimental support for selected candidates, but broader functional validation in primary AC tissues and cells is required.
PMID:
42964210
Bibliographic data and abstract were imported from PubMed on 31 Oct 2026.
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