Targeting FSP1 to induce ferroptosis in cancer: From mechanisms to therapeutic strategies

Abstract

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation. Inducing ferroptosis in tumor cells has emerged as a crucial strategy for cancer treatment and overcoming therapeutic resistance. Ferroptosis suppressor protein 1 (FSP1), identified in recent years, is a key ferroptosis-inhibitory factor that operates independently of glutathione peroxidase 4 (GPX4). FSP1 is highly expressed in multiple malignant tumors, and its expression levels are tightly associated with unfavorable patient prognosis, treatment resistance, and tumor progression. Specific stresses within the tumor microenvironment, including hypoxia, metabolic stress, and the development of drug resistance, can drive a shift in ferroptosis resistance mechanisms from GPX4-dependent to FSP1-dependent pathways. Such plasticity renders FSP1 a druggable target in specific cancer genotypes or at particular stages of tumor progression. Indeed, genetic or pharmacological inhibition of FSP1 has yielded potent antitumor effects across diverse preclinical models. This review systematically summarizes the structural characteristics of FSP1, the molecular mechanisms through which it suppresses ferroptosis, the multilayered regulatory networks controlling its activity, and its roles in different malignancies. We deeply analyze the plasticity of FSP1 dependency in tumor cells in vivo and comprehensively review the latest preclinical progress on small-molecule FSP1 inhibitors and related combinatorial therapeutic strategies. This review aims to establish a theoretical framework to support the clinical translation of FSP1-targeted antitumor strategies.