Biology subjects

Choudhury, F. K.

Publications and source records attributed to Choudhury, F. K..

3 recordsLinked to original sources

bioRxiv2026

NRF2-driven thiol metabolism creates a selective vulnerability to selenite

NRF2 hyperactivation caused by mutations in KEAP1 or NFE2L2 occurs in 20-30% of non-small cell lung cancers and confers therapy resistance. Here we show that NRF2-driven metabolic reprogramming creates a selective vulnerability to selenite. NRF2-dependent thiol export promotes the extracellular reduction of selenite to selenide. Our data support a model in which selenide enters cells and reaches mitochondria, where sulfide-quinone oxidoreductase uses selenide and glutathione to generate the selenopersulfide GS-SeH. A four-hour pulse of selenite was sufficient to induce cell death after washout, consistent with a selenium redox cycle that consumes NADPH and regenerates selenide. Within hours, selenite abolished aconitase activity and impaired mitochondrial respiration. The resulting cell death occurred independently of apoptosis, ferroptosis, pyroptosis, necroptosis and disulfidptosis. In mice, a selenite-rich diet selectively suppressed the growth of NRF2-hyperactive tumors. These findings identify an NRF2-driven metabolic vulnerability and support further investigation of selenite as a therapeutic strategy for NRF2-hyperactive cancers.

cancer biology↗

bioRxiv2026

Cancer cells acquire cysteine directly from a reduced tumor microenvironment

The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.

cancer biology↗

bioRxiv2022

Discovery of thyrocyte heterogeneity reveals an essential role of Notch signaling in thyroid function and mammalian homeostasis

The thyroid functions at the apex of a web of endocrine organs that control cell growth, differentiation and metabolic homeostasis. Thyroid dysregulation significantly impacts human health in myriad ways with thyroid diseases standing as the most common endocrine disorder. Despite the essential role of the thyroid in human health, a high-resolution view of the cellular composition as well as molecular mechanisms that govern function of this crucial organ have been lacking. Employing the first single-cell analyses of adult mouse thyroid, we here report the discovery of unexpected thyrocyte heterogeneity, specifically three distinct thyrocyte subtypes marked by different metabolic and Notch signaling patterns. Using a battery of pharmacologic and genetic methods, we find that selective inhibition of Notch ligands and receptors disrupts thyrocyte mitochondrial activity and ROS production, thus decreasing levels of circulating thyroid hormones, inducing hypothyroidism and disrupting whole-body thermoregulation. We find an enriched frequency of hypothyroidism in children with Alagille Syndrome, a genetic disorder marked by Notch loss-of-function mutations, suggesting that our Notch-thyroid mechanisms are relevant in humans and directly account for Alagille hypothyroidism. Overall, our work reveals that Notch, although classically described as a developmental pathway that determines cell fate, controls homeostasis and thermoregulation in the adult through a mitochondria-based mechanism in a subset of thyrocytes. Our fine-grained picture of the thyroid unveils a novel understanding of this key metabolic organ and provides clinically impactful insights into its pathological dysfunctions.

cell biology↗