Metabolic Repression of Autophagy Drives Inflammation, Pain, and Malodor in Hidradenitis Suppurativa

ABSTRACT Hidradenitis suppurativa (HS) is a debilitating and underdiagnosed inflammatory skin disease with limited therapeutic options due to an incomplete understanding of its molecular and immunopathogenic basis. Using an integrated multi-omics approach, we delineate convergent pathways linking dysregulated autophagy, malodour, and pain in HS. Lesional tissues exhibited sustained autophagy repression, marked by increased expression and activation of mTOR and ZKSCAN3, reduced levels of autolysosome-promoting metabolites β-hydroxybutyrate and nicotinamide riboside, and accumulation of fructose-1,6-bisphosphate, a negative regulator of AMPK. Transcriptomic analyses identified cadaverine derivatives as key metabolic drivers of keratinocyte reprogramming, inducing gene networks associated with hyperproliferation, inflammation, fibrosis, nociception, and the characteristic carrion-like odour of HS. Concordantly, ATAC-seq revealed increased chromatin accessibility at loci encoding TRP channels and histamine receptors, consistent with heightened nociceptive signalling. Multi-layered proteomics, phospho-proteomics, kinomics, and spatial proteomics analyses, validated by high-resolution confocal imaging, demonstrated elevated mTOR (Ser2448), ZKSCAN3, and P62, alongside reduced LAMP1, across keratinocytes and immune cell populations including CD4⁺ T cells, CD56⁺ NK cells, and CD68⁺ macrophages. Inhibition of mTOR normalized transcriptional programs and cytokine production linked to NLRP3 inflammasome, restoring tissue homeostasis. Collectively, these findings identify a metabolically reinforced mTOR–ZKSCAN3 axis in autophagy dysregulation and cadaverine-driven epithelial reprogramming as central mechanisms sustaining inflammation, pain, and fibrosis in HS. Highlights We identified BCAAs, BHB, NR, and FBP as key metabolites linked to mTOR activation and autophagy dysregulation in HS. Polyamines like cadaverine and putrescine, their acetylated derivatives, LPCs, and endocannabinoid dysregulation likely drive malodor and pain in HS. Cadaverine treatment of Ker-CT cells induces HS-associated gene signatures of inflammation, fibrosis, and pain. Identification of an HS macrophage subpopulation expressing ZKSCAN3 with activated mTOR and impaired autophagy.