Biology subjects

Demir, A. Y.

Publications and source records attributed to Demir, A. Y..

3 recordsLinked to original sources

bioRxiv2026

A pan-cancer benchmark of integrated ferroptosis, cuproptosis and disulfidptosis prognostic signatures

Integrated prognostic signatures combining ferroptosis, cuproptosis, and disulfidptosis are increasingly reported in oncology as advances in risk stratification, yet their added value over simpler pathway-specific or proliferation-related models remains unclear. Here, we developed an integrated regulated cell-death signature and evaluated it through an adversarial pan-cancer benchmark. Using the TCGA pan-cancer cohort comprising 9,808 tumours across 33 cancer types, we curated 118 genes associated with the three cell-death programmes, characterised inter-pathway crosstalk, and derived a 26-gene LASSO-Cox risk signature. The model showed reproducible prognostic performance across cancers, with a pan-cancer concordance index of 0.573 (95% CI, 0.552-0.594), and was independently validated in METABRIC and CGGA cohorts, remaining significant after adjustment for standard clinical variables. However, benchmarking revealed that the integrated signature, although superior to size-matched random gene sets (empirical p < 0.001), did not outperform a ferroptosis-only model (DeLong p = 0.81), indicating no measurable gain from pathway integration. Moreover, much of the prognostic signal reflected tumour proliferation rather than regulated cell death. After adjustment for the proliferation meta-signature (meta-PCNA), ferroptosis performance declined from 0.573 to 0.504, while the integrated model decreased to 0.554. High-risk tumours were more sensitive to anti-proliferative drugs, and the risk score was most strongly associated with E2F, MYC, and G2M target programmes. The signature stratified prognosis but did not predict immune-checkpoint blockade response in IMvigor210 (AUC {approx} 0.50). Importantly, the underlying biology was not merely a modelling artefact. Signature genes showed concordance with protein abundance in CPTAC cohorts, and the three cell-death programmes co-varied within individual malignant cells, with correlations ranging from {rho} = 0.46 to 0.66. Overall, our findings indicate that integrated multi-death signatures are reproducible and biologically grounded, yet prognostically redundant and substantially confounded by proliferation. This study provides a cautionary benchmark for the rapidly expanding use of composite regulated cell-death signatures in cancer prognosis.

bioinformatics↗

bioRxiv2026

The Cytochrome b m.14849T>C (S35P) Variant Induces Structural and Dynamic Alterations in the Heme bL Microenvironment in Multisystem Disease

Mitochondrial Complex III dysfunction is frequently associated with pathogenic variants in the MT-CYB gene, yet the functional consequences of many missense substitutions remain unresolved because they are classified as variants of uncertain significance (VUS). One such variant, m.14849T>C (p.Ser35Pro), has been reported in patients with multisystem mitochondrial phenotypes, including septo-optic dysplasia, cardiomyopathy, and exercise intolerance, although its structural impact on Cytochrome b function remains unclear. In this study, we employed 300 ns all-atom molecular dynamics simulations to assess structural and energetic consequences of the S35P substitution in the Cytochrome b subunit of human mitochondrial Complex III. The S35P variant did not induce global destabilization of the protein scaffold but instead promoted localized perturbations within the heme bL microenvironment. The mutation was associated with loss of a heme-proximal hydrogen-bonding network involving Ser35 and a decrease in electrostatic interaction energy between the protein matrix and the heme bL cofactor. Radial distribution function analysis further supported loosening of local packing around the prosthetic group. Consistent with these local changes, dynamics analyses indicated increased flexibility in distal transmembrane helices that form the heme-pocket scaffold and greater variability in the inter-heme Fe(bL)-Fe(bH) distance. Together, our findings suggest that S35P may exert functional effects by reorganizing the heme bL microenvironment rather than by inducing large-scale structural destabilization, underscoring the value of structure- and dynamics-based evaluation for mitochondrial VUS and suggesting a plausible mechanistic link to the pathophysiology of multisystem mitochondrial diseases.

biophysics↗

bioRxiv2025

Host iron deficiency protects against Plasmodium infection and drives parasite molecular reprofiling.

Iron deficiency, anemia and Plasmodium infection represent significant global health challenges with overlapping geographical distributions, particularly affecting pregnant women in Africa, yet the mechanisms underlying their interactions remain poorly understood. We employed a multilayered approach combining clinical data from Malawian pregnant women (n=711) in the REVAMP trial, a genetic mouse model (Tmprss6-knockout), and in vitro P. falciparum cultures to clarify associations between iron status and malaria susceptibility. Iron deficiency was associated with 50% reduced P. falciparum parasitemia in pregnant women (95% CI [30%-64%], p<0.0001), while iron-deficient mice exhibited significantly improved survival against P. berghei (median 15.5 days vs. 7.0 days for WT mice) and protection from cerebral malaria (83% vs 17% survival). Iron chelation induced substantial transcriptomic and proteomic changes in cultured parasites, affecting host cell invasion and nutrient acquisition processes. Importantly, intravenous iron supplementation did not increase subsequent parasitemia when coupled with malaria prevention. These findings demonstrate that iron deficiency protects against Plasmodium infection and support WHO recommendations for iron supplementation in malaria-endemic regions when combined with adequate malaria prevention strategies.

cell biology↗