Ferroptosis is a type of regulated cell death driven by iron-dependent phospholipid peroxidation. A recent review by Zemnou and Ngakam comprehensively summarized the regulatory network of ferroptosis and its implications in cancer, neurodegenerative diseases, and drug development. This review illustrates that ferroptosis is not merely a consequence of increased reactive oxygen species but rather a failure to maintain homeostasis involving redox-active iron, oxidizable phospholipids, and compartmentalized antioxidant defenses. The context-dependent biology of ferroptosis underlies the complexity of its therapeutic modulation: inducing ferroptosis may eliminate therapy-resistant cancer cells, while inhibiting ferroptosis may protect vulnerable neurons in neurodegenerative diseases. However, clinical translation remains limited by the absence of validated biomarkers, insufficient pharmacological selectivity, and opposing responses among different cell populations. Future development should therefore move from nonspecific modulation toward disease-specific dependencies, cell-type-resolved biomarkers, and targeted, controllable therapeutic interventions.
Objective: To elucidate the complex causal relationship and shared genetic architecture between major depressive disorder (MDD) and polycystic ovary syndrome (PCOS) through large-scale genetic analyses across diverse populations. Data Sources: Data were obtained from European and East Asian populations, including those with PCOS (defined by National Institutes of Health/Rotterdam or International Classification of Diseases criteria) and MDD (based on established criteria), along with healthy controls. Data Synthesis: In European populations, genetically predicted MDD increased the risk of PCOS [odds ratio (OR) = 1.449, 95% confidence interval (CI): 1.240 to 1.693, P = 3.02 × 10 −6 ], whereas the reverse causal effect of PCOS on the risk of MDD was statistically significant but extremely modest (OR = 1.024, 95% CI: 1.008 to 1.041, P = 3.94 × 10 −3 ). The MDD-to-PCOS association was replicated in East Asian populations with a reduced effect size (OR = 1.192, 95% CI: 1.061 to 1.340, P = 3.07 × 10 −3 ); however, the reverse association was not observed. Using Association analysis based on SubSET (ASSET) analysis, we identified 263 non-human leukocyte antigen pleiotropic loci following FUMA locus merging, including 6 novel loci (e.g., TEX41 and DDX60L). MAGMA revealed that pleiotropic single-nucleotide polymorphisms identified by ASSET were significantly enriched in 17 key pathways. Conclusion: These findings support screening for MDD in individuals with PCOS, while the reverse causal effect was modest and population specific, highlighting the importance of ancestry-aware approaches in clinical translation. The identified shared genetic pathways provide novel targets for mechanistic research and potential therapeutic development. The observed population heterogeneity emphasizes the need to develop ancestry-specific clinical approaches.
The rapid advancement of ionomics has substantially enhanced our understanding of ion homeostasis networks in living systems. However, systematic investigations of rubidium (Rb + ) remain relatively limited. Accumulating evidence suggests that Rb + not only is a chemical analog of potassium (K + ) but also may participate in a range of biological processes, including neural regulation, transmembrane ion transport, and ecological cycling, indicating the existence of distinct homeostatic regulatory characteristics. In this context, we propose the concept of rubidium ionomics, an emerging interdisciplinary field that investigates the abundance, chemical speciation, spatial distribution, dynamic transport, homeostatic regulation, and environmental fate of Rb + in biological systems. This review systematically summarizes the research scope and functional dimensions of rubidium ionomics, encompassing the distribution patterns and regulatory mechanisms of Rb + in plants, animals, microorganisms, and environmental systems. Particular attention is given to its potential roles in ion homeostasis networks, neural regulation, and biogeochemical cycling. Furthermore, we establish a methodological framework for rubidium ionomics that integrates inductively coupled plasma–mass spectrometry (ICP–MS), spatial ionomics, stable isotope tracing, multiomics integration, and computational approaches. We also discuss current challenges in model systems, data standardization, and clinical translation. In summary, rubidium ionomics represents an important extension of ionomics and elemental biology and is expected to provide new theoretical foundations for research in elemental medicine, neuroscience, agriculture, and environmental biology.
Type 2 diabetes mellitus and obesity represent intertwined chronic disorders that continue to escalate globally despite advances in pharmacotherapy. Current treatment strategies increasingly recognize the need to address both glycemic dysregulation and excess adiposity to meaningfully reduce long-term cardiometabolic risk. While glucagon-like peptide-1 receptor agonists significantly improve outcomes, many patients fail to achieve durable normoglycemia or substantial weight reduction. Tirzepatide is a novel therapeutic agent designed to activate both glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors within a single molecular framework. By engaging complementary incretin pathways, tirzepatide produces enhanced metabolic effects that extend beyond those observed with selective receptor agonists. Clinical evidence from the SURPASS and SURMOUNT programs has revealed marked improvements in glycemic control, body weight, and multiple cardiometabolic parameters with tirzepatide treatment. This review examines the physiological basis, molecular design, pharmacological properties, and clinical performance of tirzepatide, focusing on its implications for the evolving management of diabetes and obesity. The emergence of dual-incretin agonism represents a meaningful advancement toward integrated metabolic disease control.
Ferroptosis is a regulated form of cell death driven by iron-dependent phospholipid peroxidation. Since its formal description just over a decade ago, this process has emerged as a central link between fundamental cell biology and the pathophysiology of diverse clinical conditions, including cancer, neurodegeneration, ischemia–reperfusion injury, organ fibrosis, metabolic disorders, and infectious diseases. The molecular architecture of ferroptosis is centered on 4 interconnected axes: iron metabolism and labile iron pool dynamics; biosynthesis and oxidation of polyunsaturated fatty acid-containing phospholipids; the glutathione–glutathione peroxidase 4 reductive defense system; and parallel surveillance pathways, including the ferroptosis suppressor protein 1–coenzyme Q and GTP cyclohydrolase 1–tetrahydrobiopterin circuits. This review synthesizes the current mechanistic understanding of these networks, critically evaluates the pathophysiological roles of ferroptosis across major organ systems, and assesses the therapeutic landscape, which encompasses ferroptosis-inducing strategies for cancer and ferroptosis-inhibiting approaches for treating degenerative and ischemic diseases. We also discuss challenges to clinical translation, notably the absence of validated biomarkers, the context-dependent regulation of ferroptosis, and the need for tissue-selective pharmacological interventions. By integrating perspectives from cell biology, redox biochemistry, lipid metabolism, immunology, and pharmacology, this review provides a cross-disciplinary framework for understanding ferroptosis as both a fundamental biological process and a target for therapeutic intervention.
