Efferocytosis-Related Transcriptional Dysregulation in Hidradenitis Suppurativa Lesional Macrophages: A Multi-Cohort...

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease in which inflammation progresses to tunnels and fibrosis rather than resolving. Efferocytosis, the macrophage clearance of apoptotic cells, is a central mechanism of inflammation resolution, but its transcriptional status in HS is uncharacterized. We investigated whether an externally derived 167-gene efferocytosis-related panel (ER167) is transcriptionally perturbed in HS. Methods: Public Gene Expression Omnibus datasets were assigned non-overlapping roles. The primary endpoint was a donor-level, mixed-direction gene-set test of ER167 in monocyte/macrophage pseudobulk from a discovery single-cell RNA-sequencing (scRNA-seq) cohort, benchmarked against 10,000 expression- and detection-matched random panels and compared with established efferocytosis and inflammation gene sets. Analyses extended to independent scRNA-seq replication, three bulk-tissue cohorts, and 12-week adalimumab and brodalumab data. Results: In discovery macrophages, 141 of 167 ER167 genes were detected, and 62 were differentially expressed (36 increased, 26 decreased; mixed-direction p = 8.56 × 10^-7). The observed statistic exceeded all 10,000 matched random panels (empirical p = 1/10,001). This was not specific to ER167: canonical efferocytosis gene sets (p = 0.0038 and 0.0054) and the Hallmark inflammatory-response set (p = 1/10,001) also exceeded their matched nulls, whereas interferon-response sets did not. The ER167 signal replicated in an independent scRNA-seq cohort (empirical p = 0.0296) and was present at whole-tissue level in three bulk cohorts (p = 8.56 × 10^-8, 9.75 × 10^-11, 2.39 × 10^-9). No ER167 change was detectable at week 12 of biologic treatment (p = 0.378 and 0.754). Conclusions: HS lesional macrophages show a reproducible, mixed-direction perturbation of efferocytosis-related genes that accompanies an equally strong general inflammatory-response signal; no change was detectable after 12 weeks of biologic therapy. Transcript abundance does not measure efferocytic function; functional studies are required.