The roles of sirtuins in ferroptosis

Abstract

Ferroptosis represents a novel non-apoptotic form of regulated cell death that is driven by iron-dependent lipid peroxidation and plays vital roles in various diseases including cardiovascular diseases, neurodegenerative disorders and cancers. Plenty of iron metabolism-related proteins, regulators of lipid peroxidation, and oxidative stress-related molecules are engaged in ferroptosis and can regulate this complex biological process. Sirtuins have broad functional significance and are targets of many drugs in the clinic. Recently, a growing number of studies have revealed that sirtuins can participate in the occurrence of ferroptosis by affecting many aspects such as redox balance, iron metabolism, and lipid metabolism. This article reviewed the studies on the roles of sirtuins in ferroptosis and the related molecular mechanisms, highlighting valuable targets for the prevention and treatment of ferroptosis-associated diseases.

NAD+ precursors promote the restoration of spermatogenesis in busulfan-treated mice through inhibiting Sirt2-regulated ferroptosis

“…Since Npre supplementation results an increase in blood NAD + level ( Figure S1 B), and the GO terms of cluster 7 suggested upregulation of NAD + pathways in both Npre and BU+Npre (Figure 4 D), and considering that sirtuins, a family of NAD + -dependent deacetylases, play a crucial role in ferroptosis and spermatogenesis 29 , 30 , we investigated whether these latter were involved in the beneficial effects exerted by Npre on spermatogenesis.…”

“…In line with these, here, our study observed that the up-regulation of GPX4 and the down-regulation of ACSL4 caused by Npre were counteracted upon suppression SIRT2 expression. A growing number of researches have highlighted that the essential role of SIRT2 in lipid metabolism and oxidation, oxidative stress, and Fe 2+ transport 29 , 48 , suggesting its potential involvement in regulating various biological processes associated with ferroptosis. In terms of lipid metabolism, some studies have reported that SIRT2 decreased the PGC-1α protein level, which further inhibits fatty acid oxidation 49 .…”

Sodium–Glucose Transporter 2 (SGLT2) Inhibitors and Iron Deficiency in Heart Failure and Chronic Kidney Disease: A Literature Review

“…Another target of SIRT1 is nuclear factor erythroid2-related factor 2 (NRF2), which prevents lipid peroxidation, another key contributor to ferroptosis. SIRT1 can manifest anti-ferroptotic effects through the activation of NRF2, a key regulator in the antioxidant stress response, which also affects iron metabolism as it enhances ferritin formation and induces ferroportin [83]. Together, these discoveries demonstrate that NRF2 can efficiently suppress ferroptosis.…”

“…Importantly, SIRT1 over-expression induced by SGLT2 inhibitor treatment can suppress ferroptosis and prevent these deleterious consequences of increased cytosolic iron [81,82]. SIRT1 has recently been shown to control ferroptosis by influencing various target genes, among which is p53, the deacetylation of which suppresses ferroptosis [83]. Indeed, many lines of evidence indicate the crucial role of SIRT1 in the regulation of ferroptosis.…”