Targeting oxidative stress-NLRP3-apoptotic-steroidogenic axis in doxorubicin-induced testicular toxicity: protective efficacy of ferulic acid niosomes

Abstract Doxorubicin (DOX) is a commonly prescribed chemotherapeutic agent whose clinical application is limited by its toxicity to rapidly dividing organs, particularly the testes.This study explored the protective potential of ferulic acid-loaded niosomes (FA-NIO) against DOX-induced testicular dysfunction in rats and elucidated the underlying molecular mechanisms. Forty male rats were allocated into four groups: Group 1 was given saline, Group 2 was given DOX, Group 3 was given DOX + free FA, and Group 4 was given DOX + FA-NIO. Serum reproductive hormone levels, testicular oxidative stress indices, and the expression of genes and proteins relevant to NLRP3 inflammasome signaling, apoptosis (Bax and Bcl-2), and steroidogenesis (StAR, CYP11A1, and 3β-HSD) were assessed, along with histopathological changes in the testicular tissue. DOX administration significantly increased MDA (malondialdehyde) while suppressing antioxidant defences, accompanied by hormonal imbalance, severe histopathological damage, upregulation of Bax, NLRP3, and IL-1β, downregulation of Bcl-2, and inhibition of steroidogenic gene expression. On the other hand, these changes were partially mitigated in the DOX + free FA group. Notably, FA-NIO treatment reduced histopathological damage, normalised reproductive hormone levels, markedly increased steroidogenesis-related gene expression, suppressed apoptotic and inflammasome-related gene expression, and greatly restored antioxidant capacity. Compared with DOX + free FA, FA-NIO consistently demonstrated greater protective efficacy. In summary, FA-NIO targets oxidative stress-mediated apoptosis, attenuates NLRP3 inflammasome-related signaling, and restores steroidogenic function, thereby successfully attenuating DOX-induced testicular toxicity. These results suggest that FA-NIO may represent a promising nanotherapeutic strategy for attenuating chemotherapy-induced reproductive toxicity in a rat model.