Nitro Dihydrocapsaicin Attenuates Hyperosmotic Stress-Induced Inflammation in the Corneal Epithelial Cells via...

A hyperosmotic tear is a central pathogenic factor in dry eye disease (DED) that triggers inflammation, epithelial apoptosis, and structural damage to the corneal epithelium, accompanied by visual disturbances. The transient receptor potential vanilloid 1 (TRPV1) channel, which is highly expressed in corneal epithelial cells, acts as an osmosensor. N-(4-hydroxy-3-nitrobenzyl)-8-methylnonanamide, or nitro dihydrocapsaicin (NDHC), a synthetic TRPV1 agonist, has been investigated for its protective effects against hyperosmotic stress in human corneal epithelial cells (HCECs). Our results demonstrated that an increase in osmotic strength above 480 mOsM markedly caused cell death, as indicated by elevated lactate dehydrogenase (LDH) release and unexpected cell swelling rather than shrinkage, consistent with TRPV1-mediated ionic imbalance. Pretreatment with NDHC mitigated cell swelling, preserved epithelial morphology, and reduced lactate dehydrogenase (LDH) release. Transcriptomic profiling revealed that NDHC significantly reduced the number of differentially expressed genes and partially restored gene signatures, particularly within the TNFα signaling via NF-κB and MTORC1 pathways. Mechanistically, NDHC desensitized TRPV1 activation and activated the SIRT1/Nrf2/HO-1 axis, leading to the suppression of proinflammatory molecules, including IL-6, TNFα and nitric oxide. These effects were abolished by the TRPV1 inhibitor capsazepine, confirming the TRPV1 dependence. In conclusion, NDHC exhibits considerable potential as a dual-therapeutic agent against hyperosmotic stress-induced inflammation in HCECs by modulating TRPV1 activity and attenuating NF-κB-driven inflammation through the enhancement of the SIRT1/Nrf2/HO-1 cascade. These findings suggest that NDHC is a promising therapeutic candidate for alleviating epithelial damage and inflammation in DED.