Fifth research Intermittent fasting restores fertility dysfunction caused by a high-fat diet in male rats: role of SIRT-1/NRF2/P38 MAPK/NLRP3 ABSTRACT Context Intermittent fasting (IF) is a dietary approach against obesity; however, investigations on its role in male fertility showed contradictory results. Aims As nuclear factor erythroid 2-related factor 2 (NRF2)/mitogen-activated protein kinase p38 (MAPK)/nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) signaling pathways regulate inflammation and pyrotosis, this study aimed to elucidate whether these pathways are involved in the underlying molecular mechanisms and to investigate the prophylactic effects of IF on male reproduction dysfunction in obese rats. Methods Twenty-four adult rats were divided as follows: Control lean (CL), control positive (CP), which were fed standard diet for four non-consecutive days/week, with alternate fasting on the other 3days (24h fasting), high-fat diet group (HFD), and the HFDfasting group (HFD-IF), which was fed a HFD, followed by fasting protocol as in CP group. Serum testosterone, inflammatory markers, semen analysis, testicular malondialdehyde (MDA) concentration, and superoxide dismutase (SOD) activity were measured. Also, testicular and epididymal histological study, immunohistochemical analysis of NLRP3 and NRF2 and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for mRNA expression of SIRT1, NRF2, p38AMPK and NLRP3 were performed. Key results Combining IF with HFD limited rats' testicular spermatic and steroidogenesis impairment, histopathological alterations, by upregulating SIRT1/NRF2 and downregulating p38 MAPK/NLRP3 signaling pathways versus the HFD group. In the HFD-IF group, oxidative and inflammatory markers had a significant decrease versus in the HFD group. Conclusions IF has a beneficial effect on male reproductive health and emphasizes the significance of customized dietary strategies for addressing male fertility issues. Implications Further investigation is required to clarify more prophylactic mechanisms of IF