Extracellular matrix remodeling and regulated cell-death-immune associations in adhesive capsulitis: a three-cohort transcriptomic analysis
- 1Department of Integrated Traditional Chinese and Western Medicine and Rheumatology, Dianjiang People’s Hospital of Chongqing , ,
- 2Department of Traditional Chinese Medicine, Yongxing Town Central Health Center , ,
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
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BibTeX
@article{huang2026extracellular,
title = {{Extracellular matrix remodeling and regulated cell-death-immune associations in adhesive capsulitis: a three-cohort transcriptomic analysis}},
author = {Lin Huang and Ling Cheng and Jin He and Rui Zhang and Xia Li and Qiurong Xia},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1951682},
url = {https://europepmc.org/article/PMC/PMC13719448},
note = {CC BY},
}
RIS
TY - JOUR
TI - Extracellular matrix remodeling and regulated cell-death-immune associations in adhesive capsulitis: a three-cohort transcriptomic analysis
AU - Lin Huang
AU - Ling Cheng
AU - Jin He
AU - Rui Zhang
AU - Xia Li
AU - Qiurong Xia
PY - 2026
DA - 2026/10/16
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1951682
UR - https://europepmc.org/article/PMC/PMC13719448
AB - Background: 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. Methods: 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. Results: 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. Conclusion: 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.
SN - 2296-634X
ER -