In this Opinion paper we have elaborated on, and proposed that NO-dependent regulation of metabolism could go beyond this direct effect and influence key mitochondrial regulators, i.e., TRAP1 and SIRT3, which are involved in cancer-associated increase of antioxidant response and metabolic rewiring (Singh et al., 2017a; Sanchez-Martin et al., 2020b). Here, TRAP1 is linked to cancer.