Mayo, T. | bioRxiv Science

bioRxiv2026

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

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 {beta}-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. HighlightsO_LIWe identified BCAAs, BHB, NR, and FBP as key metabolites linked to mTOR activation and autophagy dysregulation in HS. C_LIO_LIPolyamines like cadaverine and putrescine, their acetylated derivatives, LPCs, and endocannabinoid dysregulation likely drive malodor and pain in HS. C_LIO_LICadaverine treatment of Ker-CT cells induces HS-associated gene signatures of inflammation, fibrosis, and pain. C_LIO_LIIdentification of an HS macrophage subpopulation expressing ZKSCAN3 with activated mTOR and impaired autophagy. C_LI

immunology↗

bioRxiv2024

High variability of migration strategies in a re-established Trumpeter Swan population

BackgroundThe Interior Population (IP) of trumpeter swans (Cygnus buccinator), formerly extirpated by market hunting, was re-established in eastern North America by releasing individuals from both migratory and non-migratory populations. Their current annual movement patterns are largely unknown. Our goal was to describe their seasonal movements and quantify the proportion of the IP that is migratory, the extent and phenology of seasonal movements, and associations between movement patterns and breeding status and breeding location. MethodsWe deployed 113 GPS-GSM transmitters on IP trumpeter swans in six U.S. states and one Canadian province across the current IP breeding range. Using data from 252 swan-years, we estimated dates of migration events by segmenting the annual cycle using piecewise regression models fit to each yearly time-series of displacement from the breeding site. We fit a latent-state model to characterize population-level associations between breeding latitude and maximum extent of migration, and linear mixed models to quantify associations between individual characteristics (e.g., breeding status, sex) and migration phenology. ResultsAt the individual level, 59% of swans moved to distant non-breeding-period areas (long-distance migration, defined as moving >100 km from the breeding site), 16% exhibited regional migration (25-100 km from breeding site), 19% exhibited non-migratory but local movements (<25 km from breeding site), and 6% exhibited multiple migration strategies. Swans breeding at more-northern latitudes departed their territories earlier in autumn and returned later in the spring than those breeding at more southern latitudes. Breeding swans departed later in the autumn than non-breeders, but breeding status did not have a strong association with arrival in the spring. ConclusionIP trumpeter swans are partial migrants, with a continuum of strategies each year, from local movements to long-distance migration. Much of the variability in movement patterns was related to factors tied to natural history demands (e.g., breeding status) and response to environmental conditions (e.g., through associations with breeding latitude).

ecology↗