Molecular and therapeutic landscape of ferroptosis in skin diseases

Abstract

Regulated cell death (RCD) is a critical physiological process essential in maintaining skin homeostasis. Among the various forms of RCD, ferroptosis stands out due to its distinct features of iron accumulation, lipid peroxidation, and involvement of various inhibitory antioxidant systems. In recent years, an expanding body of research has solidly linked ferroptosis to the emergence of skin disorders. Therefore, understanding the mechanisms underlying ferroptosis in skin diseases is crucial for advancing therapy and prevention strategies. This review commences with a succinct elucidation of the mechanisms that underpin ferroptosis, embarks on a thorough exploration of ferroptosis's role across a spectrum of skin conditions, encompassing melanoma, psoriasis, systemic lupus erythematosus (SLE), vitiligo, and dermatological ailments precipitated by ultraviolet (UV) exposure, and scrutinizes the potential therapeutic benefits of pharmacological interventions aimed at modulating ferroptosis for the amelioration of skin diseases.

Figure 1

Ferroptosis-related mechanisms in melanoma. (A) The role of dedifferentiation, oncogenic signaling (Wnt/beta-catenin/MITF and Nrf2 pathway), and miRNAs in regulating ferroptosis in melanoma. Dedifferentiation regulated by MITF promotes the melanoma cells’ vulnerability to ferroptosis. Nrf2 protects cancer cells from ferroptosis primarily through transcriptionally regulating genes involved in iron metabolism, GSH metabolism, and ROS detoxification enzymes. miRNAs have a diverse impact on ferroptotic metabolism. (B) Ferroptosis promotes melanoma metastasis both in blood and lymph. (C) Ferroptosis augments immunotherapy of melanoma by releasing IFN-γ, which promotes lipid peroxidation and ferroptosis. ACSL4: acyl-CoA synthetase long-chain family member 4; AKRs: Aldo-keto reductases; COX2: Cyclooxygenase-2; CTCs: Circulating tumor cells; Fe²⁺: Ferrous iron; FINs: Ferroptosis inducers; FTH1: Ferritin heavy chain 1; GOT1: Glutamic-oxaloacetic transaminase 1; GPX4: Glutathione peroxidase 4; GSH: Glutathione; HMOX1: Heme oxygenase-1; IFN: Interferon; miRNAs: microRNAs; MITF: Microphthalmia-associated transcription factor; MUFA: Monounsaturated fatty acid; Nrf2: Nuclear factor erythroid 2-related factor 2; OA: Oleic acid; PGC1α: Peroxisome proliferator-activated receptor gamma coactivator 1α; PUFA: Polyunsaturated fatty acid; PUFA-PL: PUFA-embedded phospholipids; PUFA-PLOOHs: PUFA-phospholipid hydroperoxides; ROS: Reactive oxygen species; SCD1: Stearoyl-CoA desaturase 1; SLC1A5: Solute carrier family 1 member 5; SREBF2: Sterol regulatory element-binding transcription factor 2; TF: Transferrin; TFR1: Transferrin receptor; TXNRD1: Thioredoxin reductase 1.

Figure 2

Ferroptosis-related mechanisms in psoriasis. (A) In the initial psoriasis stage, immune cells differentiate into Th17/22, cytokine secretion of which promotes keratinocyte lipid peroxidation. (B) Diverse gene changes in psoriasis keratinocytes promote lipid and iron metabolism, increasing the susceptibility to ferroptosis, which exaggerates inflammation via DAMPs. (C) Keratinocytes in the basal layer resist ferroptosis and indirectly promote keratinocyte proliferation, resulting in psoriasis. ACSL4: Acyl-CoA synthetase long-chain family member 4; Cyb561d2: Cytochrome b561 family member D2; DAMPs: Damage-associated molecular patterns; GPX4: Glutathione peroxidase 4; IFN: Interferon; PTGS2: Prostaglandin-endoperoxide synthase 2; PUFA-PL: PUFA-embedded phospholipids; PUFA-PLOOH: PUFA-phospholipid hydroperoxide; SLC25A28: Solute carrier family 25, member 28; SLC40A1: Solute carrier family 40 member 1; TFR1: Transferrin receptor; Zip8: ZRT/IRT-like protein 8.

Figure 3

Ferroptosis-related mechanisms in SLE. (A) The antibody and cytokine of SLE downregulate the transcription of GPX4, leading to the ferroptosis in neutrophils in SLE and promoting SLE progression. (B) B cells represent resistance to ferroptosis through upregulation of SCL7A11 and promote SLE. (C) Ferroptosis-related metabolism characteristics change in SLE, exhibiting susceptibility to ferroptosis. CaMKIV: Calcium/calmodulin kinase IV; CREMa: cAMP-responsive element modulator α; Fe²⁺: Ferrous iron; GPX4: Glutathione peroxidase 4; GSH: Glutathione; IFN: Interferon; PUFA-PLOOHs: PUFA-phospholipid hydroperoxides; SLC7A11: Solute carrier family 7 member 11; SLE: Systemic lupus erythematosus; TFR1: Transferrin receptor.