SEARCH · Search PubMed

Results for “Regulated cell death (RCD)”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

4 recordsLinked to original sources

PubMed2026

A Multi-omics Regulated Cell Death Framework Defines Immune Phenotypes and Guides Precision Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is molecularly and immunologically heterogeneous, contributing to variable treatment response. Because regulated cell death (RCD) intersects with tumor metabolism, immune regulation, and therapeutic susceptibility, we built an RCD-centered framework for CRC stratification. Multi-cohort transcriptomic data were used to infer RCD subtypes with non-negative matrix factorization (NMF) and non-negative least squares (NNLS). Genomic, bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets were integrated to characterize subtype-associated biology. Machine-learning models were developed for immunotherapy response and survival-risk estimation. Candidate compounds were screened by GDSC2-based drug-sensitivity modeling and molecular docking, and FSTL3 was functionally assessed in vitro. The framework separated CRC samples into two RCD-related phenotypes resembling immune-hot and immune-cold states. RCD1 showed immune activation and higher mutational burden, whereas RCD2 showed immune-suppressed features, intratumoral heterogeneity, and aggressive biology. RCD-associated signatures showed potential for predicting immunotherapy response and survival risk. Dasatinib was prioritized for immune-cold, high-risk tumors, with preliminary evidence supporting its activity in CRC cells, while functional assays suggested a role for FSTL3 in growth, invasion, epithelial-mesenchymal transition, and apoptosis regulation. These findings suggest that RCD-based multi-omics analysis may refine CRC stratification and help generate therapeutic hypotheses.

Colorectal cancer↗

PubMed2026

A pan-cancer multi-omic SuperLearner for regulated cell death survival topologies.

INTRODUCTION: Regulated cell death (RCD) pathways influence tumor progression and immune modulation. We previously constructed a signature database mapping 25 RCD forms across seven multi-omic layers and 33 tumor types (CancerRCDShiny). Despite their ability to identify risk populations, translating these signatures into personalized clinical workflows requires a shift from cohort stratification to individualized risk mapping by modeling patient risk (survival topologies) to capture the non-linear dynamics of RCD signatures. METHODS: We engineered a pan-cancer multi-omic SuperLearner pipeline across 33 cancer types. Phase I performed zero-leakage harmonization and groupwise imputation to prevent cross-cohort amalgamation. Phase II deployed Elastic Net-regularized Cox regression as a CANARY diagnostic to map proportional hazards failures. Strata with a 35% missingness barrier entered Phase III, deploying a Quadripartite ensemble: Random Survival Forests, XGBoost, Survival-Boruta, and Multi-Task Logistic Regression, fused within an Elastic Net Multi-View Meta-Learner (MVL), with post-hoc TreeSHAP and LIME interpretability. RESULTS: The CANARY diagnostic demonstrated the structural invalidity of pan-cancer geometric proportional hazards. Across 96 admissible strata, Phase III executed algorithmic displacement: continuous multi-omic topologies suppressed static genomic mutations and copy number variations (85.7% vs. 0.0% apex retention). The MVL stabilized predictions against extreme variance; LIME surrogate validations (R 2 < 0.10) confirmed the systematic failure of linear interpretative proxies. N-dimensional TreeSHAP interaction mapping exposed synergistic and antagonistic rescue trajectories defining individualized Survival Topologies, which were invisible to additive models. The architecture was deployed as CancerRCDPredictor, a digital molecular tumor board with integrated LLM capabilities. The MVL SuperLearner achieved a median C-index of 0.749 (IQR: 0.722-0.836) across 96 modelable strata, with 95% bootstrap confidence intervals confirming precision (median width: 0.052) and permutation significance in 93.8% of strata (p < 0.001). External CPTAC validation across ten cancer types demonstrated significant cross-cohort generalizability in clear cell renal carcinoma (KIRC; C-index 0.675, p = 0.017) and modest performance across the remaining adequately powered cancers (median 0.582), underscoring the need for larger multi-institutional validation cohorts. CONCLUSION: This pan-cancer multi-omic SuperLearner bypasses linear topological failures, advancing beyond generalized stratification to establish a deterministically mapped architecture for predicting RCD-related survival topologies. Through the CancerRCDPredictor interface, multi-omic insights translate into individualized survival topology exploration, providing a foundation for future precision oncology validation.

SuperLearner↗

PubMed2026

Necroptosis in alveolar epithelium orchestrates lung ischemia-reperfusion injury: a multi-omics study.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a leading cause of early morbidity and mortality following lung transplantation and other cardiopulmonary procedures. It is characterized by acute sterile inflammation driven by regulated cell death (RCD). While various RCD modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis, have been implicated in lung injury, their relative contributions and distinct activation patterns in LIRI remain poorly defined. METHODS: We employed an integrated multi-omics approach combining transcriptomics and proteomics with histological and functional validations in a murine hilar clamping model of LIRI. Key findings were further corroborated using single-cell RNA sequencing (scRNA-seq) data from human lung transplant recipients. The functional role of necroptosis was validated using pharmacological inhibitors (Nec-1, GSK'872) and Mlkl-deficient (Mlkl-/-) mice. RESULTS: LIRI triggered acute, time-dependent lung injury peaking within 24 h of reperfusion. Although transcriptomic profiling suggested broad activation of multiple RCD pathways, proteomic and biochemical analyses revealed a distinct landscape in our experimental setting: markers of apoptosis, pyroptosis, and ferroptosis were either downregulated or showed no significant positive correlation with injury severity and inflammatory peaks. In contrast, the necroptotic pathway emerged as a highly activated modality. Specifically, necroptosis, marked by phosphorylated RIPK1, RIPK3, and MLKL, was localized primarily in alveolar epithelial cells, correlated strongly with cytokine release and histological lung injury, and preceded the inflammatory response. Pharmacological inhibition or genetic ablation of necroptosis significantly attenuated tissue damage and inflammation. This pronounced necroptotic signature appeared distinct from the broad multi-pathway activation observed in lipopolysaccharide (LPS)-induced lung injury. Translational analysis of human scRNA-seq data further confirmed the selective upregulation of necroptosis signatures in alveolar type 2 (AT2) cells following lung transplantation. CONCLUSION: Our multi-omics analysis identifies necroptosis, particularly in alveolar epithelial cells, as a critical driver of sterile inflammation and tissue injury in the early phase of LIRI. Targeting alveolar epithelial necroptosis may represent a precise and promising therapeutic strategy for lung transplantation and ischemia-reperfusion-associated pulmonary disorders.

Animals↗

PubMed2026

Glutathione reductase deficiency potentiates the immunogenicity of ferroptosis and cuproptosis via amplified reactive oxygen species accumulation and cGAS-STING pathway activation.

BACKGROUND: Cancer remains a major therapeutic challenge due to drug resistance and metastasis, processes driven by oxidative stress and redox imbalance. Targeting this vulnerability through ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-driven mitochondrial dysfunction), two ROS-mediated cell death pathways, offers a promising therapeutic strategy. However, clinical translation is hindered by incomplete understanding of their redox regulation and limited immunogenicity. METHODS: A genome-wide CRISPR knockout screen was performed to identify key regulators of ferroptosis. Genetic depletion or pharmacological inhibition of candidate genes was evaluated across multiple cancer cell lines for sensitivity to ferroptosis inducer RSL3 and the cuproptosis inducer elesclomol (Es). Antitumor efficacy was assessed in xenograft, orthotopic, metastatic, and syngeneic mouse models, alone or combined with immune checkpoint inhibitors. Mechanistic studies also examined ROS production, mitochondrial stress, mitochondrial DNA release, cGAS-STING activation, and immune responses within the tumor microenvironment. RESULTS: Glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis. GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance. Strikingly, GSR depletion also enhanced sensitivity to cuproptosis triggered by the copper ionophore Es. In multiple in vivo tumor models, GSR inhibition synergizes with RSL3 or Es to suppress tumor growth, inhibit lung metastasis, and prolong survival. Mechanistically, GSR deficiency amplified ROS production, induced mitochondrial stress, and triggered the cytosolic mitochondrial DNA release under ferroptotic or cuproptotic stress, activating the cGAS-STING pathway in vitro and in vivo. This increased inflammatory cytokine production, promoted immunogenic cell death, and enhanced the release of damage-associated molecular patterns (DAMPs), including HMGB1. Together, GSR inhibition combined with a ferroptosis or cuproptosis inducer transformed the tumor microenvironment into a highly immune stimulatory state, thereby enhancing the efficacy of immune checkpoint blockade through increased dendritic cell activation and T-cell infiltration and activation. CONCLUSIONS: GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy.

Ferroptosis↗