Mechanisms of ferroptosis and targeted therapeutic approaches in urological malignancies

Abstract

The prevalence of urological malignancies remains a significant global health concern, particularly given the challenging prognosis for patients in advanced disease stages. Consequently, there is a pressing need to explore the molecular mechanisms that regulate the development of urological malignancies to discover novel breakthroughs in diagnosis and treatment. Ferroptosis, characterized by iron-ion-dependent lipid peroxidation, is a form of programmed cell death (PCD) distinct from apoptosis, autophagy, and necrosis. Notably, lipid, iron, and glutathione metabolism intricately regulate intracellular ferroptosis, playing essential roles in the progression of various neoplasms and drug resistance. In recent years, ferroptosis has been found to be closely related to urological malignancies. This paper provides an overview of the involvement of ferroptosis in the pathogenesis and progression of urological malignancies, elucidates the molecular mechanisms governing its regulation, and synthesizes recent breakthroughs in diagnosing and treating these malignancies. We aim to provide a new direction for the clinical treatment of urological malignancies.

Fig. 1. Mechanisms of ferroptosis.

The conversion of PUFAs to PL-PUFAs can be mediated by ACSL4 and LPCAT3. PL-PUFAs can be easily converted to PL-PUFA-OOH through various pathways, which can cause lipid peroxidation and ferroptosis. Extracellular Fe³⁺ enters the cell by binding to TF and undergoes reduction or ferritinophagy, ultimately converting into Fe²⁺ and forming the LIP. When LIP becomes overloaded with iron, it becomes prone to a Fenton reaction, facilitating lipid peroxidation and thereby triggering ferroptosis. The cysteine transported into cells by SLC7A11 can be converted into cystine, which is an essential component of GSH. GSH, mediated by GPX4, can be transformed into GSSG while reducing PL-PUFA-OOH to PL-PUFA-OH, thereby inhibiting ferroptosis. Abbreviations: PUFAs, polyunsaturated fatty acids; CoA, coenzyme A; PL-PUFAs, phospholipid-containing PUFAs; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; TF, transferrin; TFR1, transferrin receptor 1; STEAP3, iron oxide reductase steam 3; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, Oxidized glutathione; GPX4, glutathione peroxidase 4.

Fig. 2. The molecular mechanism of ferroptosis in RCC.

The modulation of ferroptosis can exert significant effects on RCC through various mechanisms, encompassing the regulation of GSH levels, lipid metabolism, iron metabolism, the NRF2 signaling pathway, the HIF-2α signaling pathway, and the ROS signaling pathway. Abbreviations: PUFAs, polyunsaturated fatty acids; CoA, coenzyme A; PL-PUFAs, phospholipid-containing PUFAs; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; TF, transferrin; TFR1, transferrin receptor 1; STEAP3, iron oxide reductase steam 3; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, Oxidized glutathione; GPX4, glutathione peroxidase 4; KLF, Kruppel-like factor; ICS II, Icariside II; DPP4, dipeptidyl-peptidase-4; NRF2, nuclear factor erythroid 2-related factor 2; OGT, O-GlcNAc transferase; HIF-2α, hypoxia-inducible factor-2α; SDH, succinate dehydrogenase; ROS, Reactive Oxygen Species.

Fig. 3. The molecular mechanism of ferroptosis in PCa.

In PCa, ferroptosis can be regulated through mechanisms involving GSH, lipid metabolism, iron metabolism, the ROS signaling pathway, and the mTOR signaling pathway. Abbreviations: PUFAs, polyunsaturated fatty acids; CoA, coenzyme A; PL-PUFAs, phospholipid-containing PUFAs; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; TF, transferrin; TFR1, transferrin receptor 1; STEAP3, iron oxide reductase steam 3; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, Oxidized glutathione; GPX4, glutathione peroxidase 4; NRF2, nuclear factor erythroid 2-related factor 2; ROS, Reactive Oxygen Species; SGK2, serum/glucocorticoid regulated kinase 2; CEMIP, cell migration-inducing protein; HnRNP L, heterogeneous nuclear ribonucleoprotein L; PHGDH, phosphoglycerate dehydrogenase; PPI, Polyphyllin I; TFEB, transcription factor EB; AOC1, amine oxidase copper-containing 1.

Fig. 4. The molecular mechanism of ferroptosis in BCa.

In BCa, ferroptosis can be regulated through various mechanisms, including GSH levels, lipid metabolism, mitochondrial metabolism, and the MAPK signaling pathway. Abbreviations: PUFAs, polyunsaturated fatty acids; CoA, coenzyme A; PL-PUFAs, phospholipid-containing PUFAs; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; TF, transferrin; TFR1, transferrin receptor 1; STEAP3, iron oxide reductase steam 3; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, Oxidized glutathione; GPX4, glutathione peroxidase 4; NRF2, nuclear factor erythroid 2-related factor 2; ROS, Reactive Oxygen Species; PHGDH, phosphoglycerol dehydrogenase; EMP1, epithelial membrane protein 1; FLRT2, fibronectin leucine rich transmembrane protein 2; PCBP1, poly C binding protein 1.