Can Ferroptosis Illuminate the Pathogenesis and Treatment of Cutaneous Diseases?

🔍 Key Finding Ferroptosis, an iron-dependent form of programmed cell death, plays a significant role in various skin diseases, including skin homeostasis, cancer, infections, genetic conditions, inflammatory disorders, and autoimmune diseases, by influencing iron metabolism, the SystemXc¯/glutathione axis, and lipid peroxidation. Further research is needed to fully elucidate the mechanisms and therapeutic potential of targeting ferroptosis in these conditions.

🔬 Methodology Overview

• Design: Narrative review.
• Data Sources: Published research literature.
• Selection Criteria: Studies related to ferroptosis and its association with various cutaneous diseases.
• Analysis Approach: Qualitative synthesis and summarization of findings related to the mechanism of ferroptosis and its connection with skin homeostasis, neoplastic diseases, infectious diseases, genetic skin diseases, inflammatory skin diseases, and autoimmune diseases.
• Scope: Focus on the role of ferroptosis in the pathogenesis, prognosis, and potential treatment of different cutaneous diseases.

📊 Results

• Skin Homeostasis: Mll4 deficiency in mouse epidermis correlates with downregulation of multiple Alox genes and impaired epidermal differentiation, suggesting ferroptosis promotes normal epidermal differentiation and barrier formation.
• Neoplastic Disease: Combined treatment with a PD-L1 blocker and cyst(e)inase enhances CTL-mediated anti-cancer effects by inducing ferroptosis. Artesunate inhibits growth of MCPyV-positive MCC cell lines via ferroptosis.
• Infectious Disease: P. aeruginosa induces ferroptosis in human bronchial epithelial cells via pLoxA expression. M. tuberculosis-induced macrophage necrosis exhibits ferroptosis features and is inhibited by ferrostatin-1 and iron chelators.
• Genetic Skin Disease: ALOX12, ALOX12B, and ALOXE3 mutations cause autosomal recessive congenital ichthyosis (ARCI). Alox12b loss-of-function mutant mice and Mll4-knockout mice exhibit ichthyosiform manifestations and altered ALOX gene expression.
• Inflammatory Skin Disease: Psoriatic lesions show elevated levels of AA metabolites, particularly 15-HpETE, and MDA. GPX4 expression is reduced in psoriatic lesions. Ferrostatin-1 reduces severity of psoriasis-like lesions in mice. UVB irradiation induces ferroptosis in keratinocytes, and NMN can enhance GPX4-mediated ferroptosis resistance.
• Autoimmune Disease: Neutrophils from SLE patients show elevated lipid peroxides and ferroptosis features, which are inhibited by ferroptosis inhibitors. Down-regulated differential circRNAs enriched in ferroptosis regulatory pathways were found in non-segmental vitiligo patients after systemic glucocorticoid treatment.

💡 Clinical Impact Gaining a deeper understanding of the mechanisms of ferroptosis and its association with dermatological disorders could illuminate the pathogenesis and treatments of different cutaneous diseases. This could lead to new therapeutic options for skin diseases like ichthyosis, psoriasis, and vitiligo, by targeting ferroptosis pathways.

🤔 Limitations

• The regulatory mechanism of ferroptosis has not been fully elucidated.
• Investigation of ferroptosis still faces challenges.
• It is currently inconclusive what specific roles ferroptosis exerts during the development of the skin and appendages.
• It is unclear what specific roles ferroptosis exerts in the pathophysiological processes of cutaneous diseases.
• It is vital to correctly determine whether ferroptosis exerts an anti- or pro-inflammatory effect on inflammation.
• It is unclear under what conditions ferroptosis has anti- or pro-inflammatory effects.
• The impact of ferroptosis on the immune system in both the short and long term needs evaluation.
• It is challenging to distinguish between different kinds of cell death.
• There is an urgency to discover markers that can specifically separate ferroptosis cells from other kinds of PCDs.
• The downstream consequences of ferroptosis are not fully understood.
• Further elucidation of the interrelationships between ferroptosis and other cell death pathways is necessary.

✨ What It Means For You Doctors should consider the role of ferroptosis in the pathogenesis and progression of various skin diseases, including neoplastic diseases, infections, genetic conditions, inflammatory disorders, and autoimmune diseases. Further research into ferroptosis mechanisms may illuminate new therapeutic targets for these conditions, potentially through modulating iron metabolism, the SystemXc¯/glutathione axis, or lipid peroxidation pathways.

Reference Liu L, Lian N, Shi L, Hao Z, Chen K. Ferroptosis: Mechanism and connections with cutaneous diseases. Front. Cell Dev. Biol. 2023;10:1079548. https://doi.org/10.3389/fcell.2022.1079548