Ferroptosis pathway components

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and membrane damage [1, 9]. It is distinct from other cell death modalities like apoptosis, necrosis, and autophagy in its morphology and biochemical requirements [3, 10]. The pathway is governed by a complex network involving iron metabolism, lipid metabolism, and antioxidant defense systems, most notably the System Xc-/GSH/GPX4 axis [1, 5]. Key enzymes like glutathione peroxidase 4 (GPX4) act to neutralize lethal lipid hydroperoxides, while ACSL4 and LPCAT3 facilitate the incorporation of oxidizable polyunsaturated fatty acids into phospholipids [1, 3]. Iron plays a catalytic role in the production of reactive oxygen species via the Fenton reaction, which drives the peroxidation process [1, 11]. In cancer therapy, inducing ferroptosis is explored as a way to eliminate therapy-resistant and metastatic cells [4, 6]. In contrast, inhibiting ferroptosis is a therapeutic goal for treating neurodegenerative diseases, such as Alzheimer's and Parkinson's, and preventing ischemia-reperfusion injury [1, 11]. Small molecules like erastin and RSL3 are well-known experimental inducers, whereas ferrostatin-1 and liproxstatin-1 are potent inhibitors used in research [2, 5]. Despite its potential, the clinical translation of ferroptosis-targeted drugs faces challenges related to systemic toxicity and the lack of validated clinical biomarkers [6, 11].

Other names

Ferroptosis regulatory networkIron-dependent cell death pathwayFerroptotic cell death pathway

Modulation of iron-dependent lipid peroxidation through the inhibition or activation of key regulatory proteins such as glutathione peroxidase 4 (GPX4), the cystine/glutamate antiporter (System Xc-), and acyl-CoA synthetase long-chain family member 4 (ACSL4).