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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: Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Studies have shown that P3H4 is a key gene underlying the malignant progression of LUAD. A potential biomarker and therapeutic target, P3H4 is involved in various cancers, but its molecular mechanism in LUAD remains unclear. Based on a series of experiments, we found that it significantly promoted the metastasis and proliferation of LUAD in vivo and in vitro. Lung cancer is associated with the greatest number of cancer-related deaths worldwide. Lung adenocarcinoma (LUAD) accounts for 85% of all cases of lung cancer. Despite recent advances in treatment, the 5-year survival rate remains less than 15%. Thus, the diagnostic and therapeutic role of LUAD remain to be further studied. The prolyl 3-hydroxylase family member 4 (P3H4) is involved in various cancers, but little is known about its role in LUAD. Our study demonstrated that the P3H4 gene was upregulated in LUAD. Clinically, the expression of P3H4 was positively correlated with an advanced TNM stage and shorter survival. Functionally, P3H4 plays a significant role in the metastasis and proliferation of LUAD both in vitro and in vivo. Mechanistically, P3H4 might interact with EGFR to regulate the metabolic substances. Our study indicated that P3H4 is a critical gene in the malignant progression of LUAD and represents a potential biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]