Disulfidptosis in cancer: from redox stress to therapeutic strategy  Nature

Se deficiency downregulates SELENOT, disrupting mitochondrial function and elevating mtROS to induce glucose metabolic reprogramming, NADPH depletion, cysteine accumulation, and disulfidptosis-mediated actin cytoskeleton collapse in chicken skeletal muscle. Interventions like SELENOT overexpression, mtROS inhibition, or NADPH supplementation partially restore redox homeostasis and NADPH function, inhibiting disulfidptosis to alleviate atrophy. These insights highlight the SELENOT/mtROS/NADPH axis for muscle wasting therapies. Abstract Skeletal muscle atrophy in poultry is characterized by reduced muscle mass and fiber quantity, leading to substantial economic losses in poultry production worldwide. Selenium is an essential trace element that maintains muscle integrity; however, the mechanisms linking Se deficiency to muscle injury remain unclear. Selenoprotein T (SELENOT) is a key regulator of cellular redox homeostasis that has not been fully characterized in skeletal muscles. Se deficiency downregulates SELENOT expression, increases oxidative stress, and induces skeletal muscle atrophy via disulfidase pathways. SELENOT deficiency impaired mitochondrial respiratory chain function, causing mitochondrial reactive oxygen species (mtROS) overproduction, glucose metabolism reprogramming, and Nicotinamide Adenine Dinucleotide Phosphate (NADPH) metabolism disruption. These changes result in cysteine accumulation and disulfidptosis, which lead to abnormal actin disulfide bonding. TEMPO-mediated mtROS inhibition or NADPH supplementation partially rescues Se-deficiency-induced muscle atrophy. SELENOT overexpression alleviates the redox imbalance, NADPH dysfunction, disulfidptosis, and myotube atrophy in Se-deficient cells, whereas rotenone-induced mtROS activation or BAY-876-mediated NADPH inhibition reverses these protective effects. The SELENOT/mtROS/NADPH axis is crucial for Se-deficiency-induced muscle atrophy. This study provides mechanistic insights into muscle-wasting disorders and potential therapeutic targets.

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8+ T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8+ T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8+ T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8+ T cells. LDHB restricts glucose-6-phosphate dehydrogenase (G6PD) activity in exhausted CD8+ T cells by interacting with G6PD, causing NADPH depletion and consequently triggering disulfidptosis. Accordingly, the loss of LDHB in T cells prevents disulfidptosis-dependent CD8+ T cell exhaustion and improves antitumour immunity. Mechanistically, STAT3 directs LDHB expression to limit G6PD activity and mediate disulfidptosis in exhausted CD8+ T cells. Our results highlight the distinct roles of disulfidptosis

Nature Reviews Molecular Cell Biology, Published online: 22 August 2025; doi:10.1038/s41580-025-00888-3In this Comment, Boyi Gan discusses disulfidptosis, a newly identified, redox-driven cell death pathway triggered by disulfide stress, and highlights its therapeutic potential while underscoring gaps in mechanistic understanding and key challenges for future research.

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Nature Reviews Molecular Cell Biology, Published online: 22 August 2025; doi:10.1038/s41580-025-00888-3In this Comment, Boyi Gan discusses disulfidptosis, a newly identified, redox-driven cell death pathway triggered by disulfide stress, and highlights its therapeutic potential while underscoring gaps in mechanistic understanding and key challenges for future research.

The involvement of lncRNA EMSLR in the disulfidptosis and progression of endometrial carcinoma  Nature

Wan, J. Shi, M. Shi, Huang et al. report a role for lactate dehydrogenase B in regulating CD8+ T cell disulfidptosis and exhaustion through the activity of glucose-6-phosphate dehydrogenase, thereby i...

I Solved Cancer, Neuroinflammation, and Mitochondrial Dysfunction. Here’s the math, and the proof. Real data. Real images. Real results.

Although disulfide stress in cancer cells under glucose starvation is known to trigger disulfidptosis, its role in the tumour microenvironment has remained unclear. A recent study in Nature Cell Biology reveals that in intratumoural CD8+ T cells, disulfidptosis promotes T cell exhaustion and thereby limits antitumour imunity.

In an era of rapidly evolving cancer therapies, the discovery of novel mechanisms driving tumor cell death offers a beacon of hope. Among these emerging modalities, “disulfidptosis” has captured the attention of scientists for its unique biochemical pathways and potential to reshape cancer treatment paradigms. A groundbreaking study published in BMC Cancer by Xu, Chen, and colleagues has meticulously charted the complex relationship between disulfidptosis and the tumor microenvironment (TME) across multiple cancer types, revealing profound prognostic implications and therapeutic opportunities.

Wan, J. Shi, M. Shi, Huang et al. report a role for lactate dehydrogenase B in regulating CD8+ T cell disulfidptosis and exhaustion through the activity of glucose-6-phosphate dehydrogenase, thereby i...

Sodium p-perfluorous nonenoxybenzenesulfonate (OBS) as a novel surrogate for perfluorooctanesulfonate (PFOS) has been extensively utilized in industrial manufacturing and daily life. However, studies on OBS-induced environmental health risks of obstructive biosynthesis (OBS) are currently limited, particularly the risk for thyroid diseases. Following the construction of in vivo (mouse) and in vitro (normal human primary thyrocytes) models of subchronic low-dose OBS exposure, we explored the thyroid-disrupting effects of OBS through multiomics approaches and experimental validations. Our results showed that subchronic exposure to low doses of OBS led to primary hypothyroidism in mice, presenting with reduced number and functional abnormalities of thyrocytes. Further in vitro assays confirmed that low-dose OBS-induced disulfidptosis, a newly discovered form of programmed cell death, in human primary thyrocytes. Meanwhile, exposure to low-dose OBS remarkably suppressed thyroid hormone synthesis pathways in mouse and human thyrocytes. The charted multiomic landscape of OBS-induced primary hypothyroidism in mammals revealed the thyroid toxicity and endocrine-disrupting properties of OBS, suggesting that it is not a safe alternative to PFOS.

Wan, J. Shi, M. Shi, Huang et al. report a role for lactate dehydrogenase B in regulating CD8+ T cell disulfidptosis and exhaustion through the activity of glucose-6-phosphate dehydrogenase, thereby i...

Disulfidptosis is a newly discovered formation of programmed cell death. However, the significance of disulfidptosis in pancreatic adenocarcinoma remains unc...

Purpose Glucose starvation induces the accumulation of disulfides and F-actin collapse in cells with high expression of SLC7A11, a phenomenon termed disulfidptosis. This study aimed to confirm the exi...