Ferroptosis, a regulated cell death modality, driven by iron-dependent lipid peroxidation, is intrinsically coupled with mitochondrial metabolic turbulence and redox dysregulation. While the mitochondrial sirtuin Sirtuin 3 (SIRT3) is canonically viewed as a master regulator of energy homeostasis, its defensive repertoire against ferroptosis extends far beyond the simplistic activation of antioxidant enzymes. In this review, we synthesize emerging evidence to construct an integrated “metabolic-structural” defense model orchestrated by SIRT3. We first delineate how SIRT3 functions as a metabolic rheostat, rewiring tricarboxylic acid (TCA) cycle flux via the deacetylation of isocitrate dehydrogenase 2 (IDH2) to sustain the nicotinamide adenine dinucleotide phosphate (NADPH)/glutathione (GSH) reservoir. Breaking away from the classical enzymatic paradigm, we highlight a novel non-enzymatic substrate regulatory mechanism where SIRT3 stabilizes the glutamate transporter SLC25A22 through specific deacetylation-ubiquitination crosstalk, thereby limiting ferroptotic susceptibility. Furthermore, we expand the SIRT3 signaling landscape by proposing a “SIRT3-nuclear factor erythroid 2-related factor 2 (Nrf2) deacetylation axis” that bridges mitochondrial stress signals to nuclear transcriptional defense, and by detailing its control over iron entry via the iron regulatory protein 1 (IRP1)-transferrin receptor 1 (TfR1) pathway. At the organelle level, we examine how SIRT3 remodels mitochondrial dynamics, upregulating optic atrophy-associated protein 1 (OPA1) while suppressing dynamin-related protein 1 (DRP1), to construct a “fusion network barrier” that dilutes ROS toxicity. We also posit a critical hypothesis: SIRT3 safeguards the integrity of mitochondria-associated endoplasmic reticulum membranes, preventing structural decoupling and calcium overload that triggers ferroptotic sensitization. Finally, we reconcile the context-dependent duality of SIRT3 in cancer and degenerative diseases, outlining future therapeutic strategies that leverage these multidimensional vulnerabilities.

Background: Glioblastoma multiforme (GBM) progression relies on active dialog between tumor cells and infiltrating immune cells, mainly including macrophages. Macrophages are closely linked to iron handling and reactive oxygen species (ROS) regulation, suggesting that ferroptosis may play a pivotal role in macrophage behavior.

Methods: Bulk RNA-seq GBM datasets, The Cancer Genome Atlas (TCGA)-GBM and gene set enrichment 4412 (GSE4412) were used to quantify immune infiltration (xCell), identify differentially expressed genes (limma), and extract ferroptosis-related markers (FerrDb V2). Ferroptosis-associated transcriptional programs were visualized using the ferroviz R package. Single-cell RNA-sequencing GBM datasets (GSE189650) were processed to characterize ferroptosis-related signatures and explore the dynamic regulation of ferroptosis-related genes in M2 tumor-associated macrophages (M2-TAMs). Deep learning neural networks were trained to predict recurrence based on ferroptosis hallmarks.

Results: High M2-TAM infiltration in poor-prognosis tumors was associated with a deregulated ferroptosis program defined by nine markers, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), arachidonate lipoxygenase 5 (ALOX5), perilipin 2 (PLIN2), spermidine/spermine-N1-acetyltransferase 1(SAT1), ferritin light chain (FTL), cathepsin B (CTSB), poly (ADP-ribose) polymerase 8 (PARP8), heme oxygenase-1 (HMOX1), autophagy-related 7 (ATG7), validated at single-cell resolution and enriched in CD16+/CD163+ myeloid cells. A ferroptosis score independently predicted M2 infiltration in a clinicobiological multivariable model. Deep learning analyses revealed opposite regulation of TNFAIP3 (repressed ferroptosis driver) and FTL (upregulated ferroptosis suppressor) during recurrence, indicating impaired ferroptosis in M2-TAMs during disease progression. TNFAIP3 expression in primary tumors aligned with a pro-inflammatory signature, whereas FTL expression in recurrent tumors correlated with an invasive program involving apolipoprotein E (APO-E), serpin family E member 1 (SERPINE1), thioredoxin-interacting protein (TXNIP), glycoprotein non‑metastatic melanoma protein B (GPNMB), cystatin C (CST3), dihydrofolate reductase (DHFR), β2-microglobulin (B2M), and nuclear protein-1 (NUPR1).

Conclusion: Glioblastoma-associated macrophages display defective ferroptosis program in aggressive and recurrent tumors, linking reduced inflammatory activity to enhanced invasiveness. Restoring ferroptosis activity in these immune cells may represent a promising therapeutic strategy.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute respiratory failure characterized by diffuse lung inflammation and edema. Despite increased understanding of the molecular biology underlying ARDS, the complex pathogenesis still limits the development of targeted pharmacologic therapies. Cell death plays a vital role in defending against pathogen infections and triggering tissue inflammation, which can damage the alveolar-capillary barrier and ultimately lead to the development of ARDS. Thus, targeting various cell death pathways may be an attractive entry point for therapeutic intervention in ARDS. Intriguingly, recent genetic and biochemical studies have emphasized the importance of revealing the crosstalk among various cell death pathways and indicated that this connectivity exhibits a considerable degree of plasticity in the molecular regulation of potential therapeutic targets in ARDS. In this review, we summarize the mechanisms of the different types of regulated cell death (RCD) and describe the physiological and pathological processes that contribute to ARDS pathogenesis. We also discuss the emerging crosstalk among various RCD modalities, and highlight that targeting cell death pathways is an effective therapeutic strategy for ARDS.

Metabolic reprogramming fundamentally drives cancer progression, with aberrant amino acid metabolism serving as a critical nexus for maintaining redox homeostasis and dictating cell fate. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, is closely related to intracellular amino acid metabolic networks. Here, we systematically delineate how key amino acids function as multi-dimensional regulatory nodes that orchestrate tumor cell susceptibility to ferroptosis. We provide a focused analysis of the context-dependent mechanisms through which these metabolic pathways rewire cellular redox capacity, modulate central anti-ferroptotic defense nodes (e.g., GPX4), and reshape the tumor microenvironment. Finally, we highlight the profound metabolic plasticity and spatiotemporal heterogeneity of these networks, exposing the intrinsic vulnerabilities within the amino acid-ferroptosis axis that drive drug resistance and tumor evolution.

Iron is essential for cellular metabolism, redox balance, and proliferation, yet its redox activity generates reactive oxygen species (ROS) that can damage DNA, proteins, and lipids. Cancer cells exploit iron homeostasis mechanisms, including iron regulatory proteins, ferritinophagy, and hypoxia-inducible factors to maintain high intracellular iron, supporting metabolic reprogramming, antioxidant defenses, and therapy resistance. Iron-dependent lipid peroxidation drives ferroptosis, a regulated form of cell death uniquely dependent on iron. Ferroptosis is tightly controlled by metabolic and antioxidant pathways and mitochondrial ROS, as well as by lipid composition and polyunsaturated fatty acid availability. Ferroptosis also intersects with apoptosis and necroptosis, highlighting the central role of iron in cell fate and survival. Dysregulation of these pathways in cancer can sensitize cells to ferroptosis, creating a therapeutic vulnerability. Exploiting ferroptosis through modulation of iron availability, redox defenses, or lipid metabolism offers a promising anticancer strategy. However, tissue-specific iron dynamics, tumor heterogeneity, and interactions within the tumor microenvironment complicate clinical translation. Integrative approaches combining metabolic profiling, genetic analysis, and ferroptosis-targeted interventions will be critical to harness iron-dependent cell death while minimizing systemic toxicity. In this review, we explore the mechanisms through which cancer cells sustain high iron, evading associated toxicities and possible implications for integrating ferroptosis based therapies in clinical oncology.

Ferroptosis has emerged over the past decade as a compelling therapeutic avenue for cancer, prompting intense interest in strategies that selectively induce or inhibit this form of cell death. Although substantial progress has been made in identifying genes that regulate ferroptosis sensitivity and in developing small-molecule modulators, it remains unclear which molecular targets offer the greatest therapeutic potential in specific tissues and contexts. Here, we highlight fundamental differences between in vitro and in vivo ferroptosis modulation, with emphasis on the integration of different techniques, mouse models, and how the tumor microenvironment shapes two major ferroptosis surveillance pathways: glutathione peroxidase 4 and ferroptosis suppressor protein 1. We propose that integrating in vivo biological constraints and microenvironmental complexity is essential for the rational design and successful translation of ferroptosis-targeted therapies.