Tetracycline reprograms inflammatory and regenerative signaling pathways in human keratinocytes exposed to Loxosceles spider venoms and sphingomyelinases

Introduction Loxosceles spider envenomation, or loxoscelism, constitutes the most severe form of araneism and frequently progresses to dermonecrosis with significant tissue damage. The key venom component, sphingomyelinase D (SMase D), drives both local and systemic effects through its structurally distinct Class I and II isoforms, each differing in toxicity. The current therapies provide limited benefit and, once necrosis is established, interventions are primarily supportive, underscoring the need for more effective pharmacological options. While tetracyclines have emerged as promising modulators of cutaneous loxoscelism in animal models, beyond their antimicrobial properties and owing to their ability to inhibit matrix metalloproteinases, the molecular mechanisms underlying their protective effects remain poorly defined. Methods This study aimed to elucidate the transcriptomic landscape of tetracycline-associated protection in human keratinocytes in response to Loxosceles venoms and SMase D Class I and II isoforms. Results Using transcriptomic profiling, we show that tetracycline upregulates SOX2 and SOX18 while downregulating IL1RL1 in keratinocytes exposed to Loxosceles venoms and SMases D. These regulatory changes are associated with reduced IL-1-mediated inflammation and activate pathways related to cell migration, epidermal morphogenesis, and tissue regeneration. Gene Ontology enrichment supported these findings, linking tetracycline treatment to biological processes of proliferation, wound closure, and repair. Furthermore, tetracycline attenuates SMase D-induced expression of pro-inflammatory and proteolytic mediators, shifting gene expression patterns toward profiles compatible with tissue homeostasis. Conclusion Collectively, these transcriptomic findings, together with our previous functional studies, support a mechanistic framework in which tetracycline mitigates venom-induced pathology and highlight its potential as a therapeutic candidate for cutaneous loxoscelism and warrants targeted functional validation in future studies.