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Simple Summary: In the complex world of cancer, iron and copper play essential roles as trace metal ions that are crucial for cancer cell survival. Disruption in their metabolic functions can be lethal to cancer cells, triggering ferroptosis and cuproptosis, respectively. Given an accelerated proliferation rate, cancer cells exhibit a heightened dependence on iron and copper, exposing vulnerabilities that could potentially be exploited to reverse drug resistance. Notably, mitochondria, the cellular powerhouses, play a crucial role in regulating both ferroptosis and cuproptosis. This review focuses on elucidating the key mechanisms behind ferroptosis and cuproptosis and summarizes recent clinical applications targeting dysfunctional iron and copper metabolic pathways. Drug resistance is a hallmark of cancer development that underscores a critical need to address it, underscoring the critical need to explore novel approaches. Understanding and targeting these metal-related processes offers promising approaches for developing innovative cancer therapies, making use of vulnerabilities specific to cancer cells. Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: ACSL4 is an enzyme involved in the intracellular conversion of long-chain fatty acids and coenzyme A into fatty-acid coenzymes. It plays a vital role in various biological processes, including maintaining cell membrane structure, energy metabolism, and lipid metabolism. Recent studies have shed light on the involvement of ACSL4 in cell death pathways, autophagy regulation, and the development of human diseases. These findings position ACSL4 as a potential therapeutic target. This review provides an overview of the fundamental structure and mechanisms regulating ACSL4 at both the gene and protein levels, emphasizing its diverse biological functions. Additionally, we discuss the role of ACSL4 in different regulated cell death modalities, including apoptosis and ferroptosis, as well as its involvement in autophagosome formation. Furthermore, we explore potential modulators targeting ACSL4 and emphasize the importance of further research to comprehensively understand the clinical impact of ACSL4 in regulating various pathological conditions. By addressing concerns regarding the systemic impact of therapeutic approaches targeting ACSL4, we aim to pave the way for the development of effective treatments for human diseases. Lipid metabolism, cell death, and autophagy are interconnected processes in cells. Dysregulation of lipid metabolism can lead to cell death, such as via ferroptosis and apoptosis, while lipids also play a crucial role in the regulation of autophagosome formation. An increased autophagic response not only promotes cell survival but also causes cell death depending on the context, especially when selectively degrading antioxidant proteins or organelles that promote ferroptosis. ACSL4 is an enzyme that catalyzes the formation of long-chain acyl-CoA molecules, which are important intermediates in the biosynthesis of various types of lipids. ACSL4 is found in many tissues and is particularly abundant in the brain, liver, and adipose tissue. Dysregulation of ACSL4 is linked to a variety of diseases, including cancer, neurodegenerative disorders, cardiovascular disease, acute kidney injury, and metabolic disorders (such as obesity and non-alcoholic fatty liver disease). In this review, we introduce the structure, function, and regulation of ACSL4; discuss its role in apoptosis, ferroptosis, and autophagy; summarize its pathological function; and explore the potential implications of targeting ACSL4 in the treatment of various diseases. [ABSTRACT FROM AUTHOR]

Although induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as an anticancer strategy, the metabolic basis of ferroptotic death remains poorly elucidated. Here, we show that glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc−. Mechanistically, SLC2A1-mediated glucose uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels the tricyclic acid cycle, and stimulates fatty acid synthesis, which finally facilitates lipid peroxidation-dependent ferroptotic death. Screening of a small interfering RNA (siRNA) library targeting metabolic enzymes leads to identification of pyruvate dehydrogenase kinase 4 (PDK4) as the top gene responsible for ferroptosis resistance. PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xc− inhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). These findings reveal metabolic reprogramming as a potential target for overcoming ferroptosis resistance. • SLC2A1-dependent glucose uptake facilitates ferroptosis • Pyruvate oxidation-dependent fatty acid synthesis facilitates ferroptosis • PDK4 is a key metabolic regulator of ferroptosis resistance • High-fat diet promotes ferroptotic cell death in vivo Song et al. demonstrate that PDK4 plays a role in preventing ferroptosis by inhibiting pyruvate oxidation and subsequent fatty acid synthesis and lipid peroxidation in pancreatic cancer cells. These findings indicate that targeting glucose metabolic pathways has the potential to modulate ferroptosis sensitivity in cancer therapy. [ABSTRACT FROM AUTHOR]

• Calcium homeostasis is crucial in cancer, regulating many physiological processes. • Calcium ion-related channels are crucial in cancer regulation and potential therapeutic targets. • Physiological processes like EMT, drug resistance, etc., and their association with calcium ion-related channels are critical in cancer. • Many small molecular drugs have been developed targeting those channels. Calcium ion dysregulation exerts profound effects on various physiological activities such as tumor proliferation, migration, and drug resistance. Calcium-related channels play a regulatory role in maintaining calcium ion homeostasis, with most channels being highly expressed in tumor cells. Additionally, these channels serve as potential drug targets for the development of antitumor medications. In this review, we first discuss the current research status of these pathways, examining how they modulate various tumor functions such as epithelial–mesenchymal transition (EMT), metabolism, and drug resistance. Simultaneously, we summarize the recent progress in the study of novel small-molecule drugs over the past 5 years and their current status. [ABSTRACT FROM AUTHOR]

Significance: Cholesterol is a type of lipid that plays a crucial role in building and maintaining cell membranes, producing certain hormones, and aiding in digestion. The two main types of cholesterol are low-density lipoprotein and high-density lipoprotein, and maintaining a healthy balance between them is essential for cellular function and organism health. Recent Advances: Cholesterol metabolism is a complex and dynamic process that involves biosynthesis, uptake, efflux, transport, and esterification. Disruptions in cholesterol metabolism are implicated in all stages of cancer, contributing to drug resistance, immune evasion, and autophagy dysfunction. These disruptions have also been linked to various types of regulated cell death, such as apoptosis, anoikis, lysosome-dependent cell death, pyroptosis, NETosis, necroptosis, entosis, ferroptosis, alkaliptosis, immunogenic cell death, and paraptosis. Critical Issues: Understanding the complex interplay between cholesterol metabolism and cell death and their impact on cancer development and progression is still a significant challenge. In addition, there is currently a lack of reliable biomarkers that can accurately reflect cholesterol metabolism dysregulation in cancer. Future Directions: To develop more specific and effective cholesterol metabolism-targeted therapies, a better understanding of the mechanisms by which cholesterol metabolism dysregulation contributes to cell death and cancer progression is needed. In addition, improving the accuracy and reliability of biomarkers will be crucial for monitoring and diagnosing cholesterol-related cancer subtypes and evaluating the effectiveness of cholesterol metabolism-targeted therapies. These efforts will require ongoing research and collaboration among multidisciplinary teams of scientists and clinicians. Antioxid. Redox Signal. 39, 102–140. [ABSTRACT FROM AUTHOR]

Significance: Autophagy is a self-degrading process that determines cell fate in response to various environmental stresses. In contrast to autophagy-mediated cell survival, the signals, mechanisms, and effects of autophagy-dependent cell death remain obscure. The discovery of autophagy-dependent ferroptosis provides a paradigm for understanding the relationship between aberrant degradation pathways and excessive lipid peroxidation in driving regulated cell death. Recent Advances: Ferroptosis was originally described as an autophagy-independent and iron-mediated nonapoptotic cell death. Current studies reveal that the level of intracellular autophagy is positively correlated with ferroptosis sensitivity. Selective autophagic degradation of proteins (e.g., ferritin, SLC40A1, ARNTL, GPX4, and CDH2) or organelles (e.g., lipid droplets or mitochondria) promotes ferroptosis by inducing iron overload and/or lipid peroxidation. Several upstream autophagosome regulators (e.g., TMEM164), downstream autophagy receptors (e.g., HPCAL1), or danger signals (e.g., DCN) are selectively required for ferroptosis-related autophagy, but not for starvation-induced autophagy. The induction of autophagy-dependent ferroptosis is an effective approach to eliminate drug-resistant cancer cells. Critical Issues: How different organelles selectively activate autophagy to modulate ferroptosis sensitivity is not fully understood. Identifying direct protein effectors of ferroptotic cell death remains a challenge. Future Directions: Further understanding of the molecular mechanics and immune consequences of autophagy-dependent ferroptosis is critical for the development of precision antitumor therapies. Antioxid. Redox Signal. 39, 79–101. [ABSTRACT FROM AUTHOR]