Gastric cancer (GC) is associated with poor prognosis due to its intricate molecular mechanisms that drive multiple malignant functions. While KLC3 has been found to be abnormally expressed in various tumors, its specific mechanistic role in GC remains largely unknown.

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of epithelial ovarian cancer, characterized by rapid progression and poor prognosis. Despite advances in treatment, most cases are diagnosed at an advanced stage, and current diagnostic markers such as CA-125 have limited utility for early detection or treatment stratification. This study aimed to investigate the clinical significance and biological Function of phospholipase C delta 1 (PLCD1) in HGSOC.

The human Y chromosome (ChrY), which confers male sex determination, contains a relatively small number of protein-coding genes compared to other chromosomes; consequently, its functional impact on adult physiology was once severely unappreciated. While the repetitive structure of the ChrY once impeded sequencing, technological advances have now made it possible to identify its contents. Despite the historical view of ChrY as a virtual wasteland, we now know that it encodes a variety of genes which are hugely consequential to both human health and disease. The extreme downregulation of ChrY gene expression, resulting from partial or total loss of ChrY (LOY), is a common characteristic observed in various disease states in men, including cardiovascular, neurodegenerative, immunological health issues, and ,most notably, cancer. Additionally, mosaic LOY (mLOY) is sometimes found in primary cancerous tissues and is associated with poorer clinical outcome. Although, the reasons for these associations were once elusive, they are now understood to be linked to the activity of several ChrY genes, as well as the pleiotropic effects of their loss. In this review, we critically analyze contemporary and historic scientific literature which evaluate the clinical LOY trends seen in male exclusive/predominant cancers as well as explore the now identified mechanisms of ChrY alteration in cancer initiation, progression, and metastasis. Moreover, we discuss recent research studies which have uncovered novel mechanisms through which LOY may induce the physiological and molecular changes in the tumor microenvironment (TME) associated with malignant transformation and the evasion of innate immunity. Interestingly, the TME formed by malignant cells with LOY appears to contribute to early T cell exhaustion in infiltrating immune cells and consequent compromised tumor clearance; a phenomenon which has been profusely observed in patient samples. Furthermore, we describe the tumor-suppressive activities of the ChrY demonstrated in previous studies, as well as its newly identified roles in cancer immunology.

TCL1 mice are the most commonly used preclinical model for chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by clonal CD5+ B-lymphocyte accumulation. B-cell receptor (BCR) sequencing identifies two important risk markers, immunoglobulin heavy chain variable region (IGHV) mutational status and receptor stereotypy. Despite its clinical relevance in patients, comprehensive examinations of endogenous BCR repertoires in TCL1 mice remain limited. We analysed BCR repertoires of 85 TCL1 mice, primarily comprising CLL clones using IGHV1 and IGHV11 (27.3 and 49.1% of CLL clones, respectively). Interestingly, TCL1 mice with dominant IGHV1 CLL clones showed significantly higher levels of CD4+ T-cells, and increased exhaustion levels (PD-1) on splenic CD8+ T-cells compared to IGHV11 CLL clones. Cancer related pathways (p53, MTORC and KRAS) were distinctly regulated in IGHV1 CLL clones. These clones occurred more frequently in female mice, characterized by short survival times (hazard ratio 2.6). Additionally, mice with dominant IGHV1 CLL clones displayed an almost twofold inguinal lymph node enlargement. In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL.

Cancer can result from abnormal regulation of cells by their environment, potentially because cancer cells may misperceive environmental cues. However, the magnitude to which the oncogenic state alters cellular information processing has not been quantified. Here, we apply pseudorandom pulsatile optogenetic stimulation, live-cell imaging, and information theory to compare the information capacity of receptor tyrosine kinase (RTK) signaling pathways in EML4-ALK-driven lung cancer (STE-1) and in non-transformed (BEAS-2B) cells. The average information rate through RTK/ERK signaling in STE-1 cells was less than 0.5 bit/hour, compared to 7 bit/hour in BEAS-2B cells, but increased to 3 bit/hour after oncogene inhibition. Information was transmitted by 50-70% of cells, whose channel capacity (maximum information rate) was estimated through in silico protocol optimization. In BEAS-2B cells, channel capacity of the parallel RTK/calcineurin pathway surpassed that of the RTK/ERK pathway. This study highlights information capacity as a sensitive metric for identifying disease-associated dysfunction and evaluating the effects of targeted interventions.

Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a poor prognosis and limited treatment options. Previous studies have shown that selective downregulation of the MADD (MAP-kinase-activating death domain-containing protein) gene isoform increases ATC cell susceptibility to TRAIL-induced apoptosis. However, the existence of multiple MADD gene isoforms raised the possibility of functional compensation. This study aimed to definitively evaluate the role of MADD in ATC by employing CRISPR-Cas9 to Cas9 to target exon 3, a conserved exon expressed in all known MADD isoforms, resulting in functional knockout of MADD expression. CRISPR-Cas9-mediated MADD knockout, performed in three ATC cell lines (8505 C, C643, and HTH7) with distinct mutational backgrounds, significantly impaired ATC cell function in vitro, as indicated by reduced viability, increased apoptosis, decreased migration, and G0/G1 cell cycle arrest. RNA-seq analysis revealed alterations in genes related to cell survival, proliferation, and metastasis. In the orthotopic ATC mouse model, MADD deletion dramatically suppressed tumor growth, reduced lung metastases, and prolonged survival. Our findings demonstrate that MADD plays a crucial role in ATC cell survival, proliferation, and metastasis. The consistent effects observed across multiple cell lines and in vivo models suggest that MADD may represent a promising therapeutic target for this aggressive malignancy.

High-grade serous carcinoma (HGSC) thrives in an immune-suppressive microenvironment marked by poor T-cell infiltration and blunted anti-tumor responses, driving immune evasion, tumor progression, and therapy resistance. Regulation of genomic instability, which restricts cytoplasmic DNA accumulation, is essential to prevent immune activation. Claudin-4, often overexpressed in HGSC, is strongly linked to therapy resistance and plays a key role in regulating initiation and resolution of genomic instability, shaping the tumor's potential ability to evade immune surveillance and withstand treatment; however, its role in immune evasion remains unclear. We used in vitro ovarian cancer models with stable claudin-4 overexpression and knockdown. In a humanized mouse model, ovarian tumors were treated with the claudin mimic peptide (CMP) and a PARP inhibitor. Tumor growth and immune infiltration were assessed by IVIS imaging and spectral flow cytometry. Mechanistic studies included autophagy flux and ISRE reporter assays, complemented by immunoblotting, flow cytometry, confocal microscopy, and bioinformatic analyses of public datasets. We identified a novel claudin-4-driven mechanism that promotes immune evasion in HGSC. Claudin-4 regulated type I interferon signaling through a close association with the small GTPase Rab7, modulating tumor-immune interactions. This was linked to TCR-zeta chain suppression in T cells in vivo-a hallmark of immune evasion. Dual targeting of claudin-4-expressing tumors with CMP and niraparib reshaped the tumor immune microenvironment, restoring TCR-zeta expression and promoting CD8 + T-cell infiltration, leading to improved anti-tumor efficacy of the PARP inhibitor niraparib. Our data show that claudin-4 orchestrates tumor immune evasion and survival, positioning it as a dual regulator of genome stability and immune escape, and highlighting it as a promising therapeutic target in ovarian cancer.

This study aimed to identify prognostic features in high-grade serous ovarian cancer (HGSOC) through the application of gene regulatory network (GRN) inference with single-cell RNA-sequencing (scRNA-seq) profiles. To achieve this goal, we developed a workflow comprising scRNA-seq analysis, metacell construction, GRN inference, and a binary classification task for prognosis prediction. We curated 118,173 cells from HGSOC patients in three conditions (Before-chemotherapy, After-chemotherapy, and control samples) from previous studies, and then constructed 1,211 metacells. GRN inference analysis revealed 312 regulons, each consisting of one transcription factor and its targeted features. For prognosis evaluation, we used bulk RNA-seq data covering 342 HGSOC patients from The Cancer Genome Atlas (TCGA) and defined a binary outcome of overall survival ≥ 2 years from initial diagnosis, with censored cases at last follow-up assigned to the appropriate class by observed time. We prioritized the features of the TCGA data based on regulon information and differentially expressed features extracted from the metacell data. Our results demonstrated that regulon-based prognostic features were more effective than differential expression-based features in both Before-chemotherapy and After-chemotherapy groups. Our framework can be generalized to other types of cancer when single-cell data for GRN inference and bulk RNA-seq data with clinical outcomes are available.

Gene therapy has garnered significant attention in cancer treatment. Here, we identified the long noncoding RNA LINC02178 as an oncogenic driver in lung adenocarcinoma (LUAD) and developed a nanoparticle-based small interfering RNA delivery system (NPs/2178) targeting this gene, providing novel insights for gene therapy development. Bioinformatics analysis was used to identify LINC02178 as a candidate oncogene and evaluate its clinical value. Subcellular localization of LINC02178 was determined through cytoplasmic/nuclear RNA fractionation coupled withs Reverse transcription quantitative polymerase chain reaction (RT-qPCR). The transfection efficiency of the NPs was assessed using confocal microscopy and RT‒qPCR. The biological toxicity of NPs/2178 was tested via cell Counting Kit-8 (CCK-8) and live/dead assays. Flow cytometry, 5-Ethynyl-2'-deoxyuridine (EdU), CCK-8 and colony formation assays were conducted to evaluate apoptosis and proliferation. The therapeutic efficacy and biosafety of this platform were further validated in a subcutaneous xenograft mouse model. LINC02178 expression was elevated in LUAD tissues and cell lines and correlated with advanced clinical stage and poor prognosis. Gene enrichment analysis indicated that LINC02178 was strongly related to cancer progression and apoptosis. The NPs/2178 platform achieved effective LINC02178 knockdown and demonstrated that the cytotoxicity of LUAD cells was significantly greater than that of mouse fibroblasts. The NPs/2178 gene delivery system significantly promoted LUAD apoptosis and inhibited cell proliferation in vitro. In vivo studies revealed marked tumour growth inhibition by NPs/2178 without observable systemic toxicity. LINC02178 functions as an oncogenic factor that promotes LUAD progression. The NPs/2178 delivery system represents a promising gene therapy strategy.

Curcumin has attracted attention for its nontoxic chemopreventive effects; however, the pathways underlying these effects in colon cancer remain unclear. We investigated the potential interplay between curcumin and integrin β1 in colon cancer. Human colon cancer (HCT) 116 cell line and fibroblast cells were treated with curcumin, and cell proliferation was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and western blotting. Using western blotting and confocal microscopy in curcumin-treated HCT116 cells, we analyzed integrin β1 expression and the roles of talin and rab25 in integrin β1 activation by curcumin. Curcumin significantly decreased the survival of HCT116 cells but did not significantly affect the survival of fibroblast cells. Moreover, curcumin significantly increased integrin β1 expression in HCT116 cells, which was primarily mediated by talin. In contrast, rab25 expression remained unchanged after curcumin treatment. Using rab25-specific small interfering ribonucleic acid knock-down experiments, we confirmed that curcumin increased integrin β1 expression even in the absence of rab25. Confocal microscopy revealed a dose-dependent increase in integrin β1 and talin expression, with consistent spatial distribution patterns in response to curcumin. This study reports that curcumin acts as an anticancer agent in colon cancer by modulating integrin β1 expression through a talin-mediated pathway rather than through rab25.

Merkel cell carcinomas (MCCs) are rare, highly aggressive skin cancers with poor outcome due to early lymphatic tumor spread and frequent recurrences. MCCs mostly occur in the head and neck and are mainly caused by an infection with the Merkel cell polyomavirus (MCPyV). Increasing evidence suggests that Piwil-2 and small non-coding PIWI-interacting RNAs (piRNAs) play an important role in solid malignancies and we thought that this might also be the case for MCCs. Therefore, Piwil-2 expression was first evaluated in 27 MCC specimens and correlated with oncological outcome. We found an association with high Piwil-2 expression and advanced tumor stage, MCPyV positivity and poor outcome. Next, we utilized siRNAs for Piwil-2 knock-down in MCC cells. Downregulation of Piwil-2 caused a significant change of 202 different piRNAs and 419 proteins. Interestingly, proteins related to viral driven MCC pathways (TRRAP, BRD8, PRIM2, ORC4) were significantly downregulated. Moreover, there was a moderate cell cycle arrest of cells in the G0/G1-phase, as well as a significant upregulation of SOX-2, a key regulator of Merkel cells. Altogether, Piwil-2 poses a poor prognosticator in MCCs, which is linked to MCC oncogenesis and SOX-2. Further research is needed to better understand underlying mechanisms and to prove their clinical relevance.

Despite the outstanding achievements of precision medicine in hematology, many targeted therapies eventually fail due to the emergence of resistance mechanisms. Traditionally, a genocentric approach has been adopted to uncover the molecular underpinnings of treatment resistance. This has contributed to identifying resistance gene mutations and designing novel therapeutic molecules with increased potency for the mutant target. However, over the last five years, additional non-genetic adaptations have become increasingly recognized as crucial promoters of treatment resistance. In parallel, emerging works in the field of evolutionary biology suggest that advantageous phenotypic traits appear most often due to cell-intrinsic phenotypic plasticity and can arise independently of gene mutations. In selected cases, single genetic abnormalities such as those involving TP53 can prime human cells for plasticity and facilitate phenotypic variability. In this narrative review, we retrace the resistance mechanisms to targeted therapies in the framework of these novel evolutionary concepts. We highlight the dichotomy between genes-first and phenotypes-first pathways of treatment adaptation, with the former being driven by traditional single-point mutations and the latter initiated by the phenotypic diversity and the high-level plasticity of cancer cells. Focusing on resistance mechanisms to kinase inhibitors and BH3 mimetics in leukemias and lymphomas, we describe how each drug can trigger both escape routes, which may even coexist within the tumor bulk of individual patients. Lastly, we provide a three-step translational perspective on how to counteract phenotypes-first resistance mechanisms, with the aim of prolonging disease control in hematological malignancies.

Human isotopic tracer studies are key for in vivo studies of cancer metabolism. Yet, the effects of sampling conditions on the tissue metabolome remain understudied. Here, we perform a 13C-glucose study coupled with metabolomic, transcriptomic, and proteomic profiling in patients with clear cell renal cell carcinoma (ccRCC) to assess the impact of ischaemia on tissues sampled intraoperatively and post-surgical resection, where tissues are exposed to varying degrees of warm ischaemia. Although several metabolic features were preserved, including suppressed TCA cycle activity, ischaemia masked other metabolic phenotypes of ccRCC, such as suppressed gluconeogenesis. Notably, normal kidneys were more metabolically susceptible to ischaemia than the ccRCC tumours. Despite their overall stability, ischaemia caused subtle changes in the proteome and transcriptome. Using orthotopic ccRCC-derived xenografts, we evidenced that prolonged ischaemia disrupted the tissue metabolome stability. Overall, minimising tissue ischaemia is pivotal in accurately profiling cancer metabolism in patient studies.

Colorectal cancer (CRC) is the third most common cancer worldwide and a significant public health threat. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising therapeutic target in CRC treatment. Despite its significant clinical potential, the precise regulatory mechanisms underlying ferroptosis, particularly its role in ferroptosis within CRC, remain to be fully elucidated. Previous studies, including our own work, have revealed that various deubiquitinases (DUBs) are involved in regulating cellular processes; however, the specific mechanisms by which these enzymes contribute to ferroptosis in CRC remain unclear. In this study, we identify USP5 as a key regulator of ferroptosis in CRC. Traditionally recognized as a deubiquitinase, USP5 modulates cellular physiological activities through deubiquitination. However, our findings show that USP5, distinct from its conventional deubiquitination function, suppresses ferroptosis by promoting the lysosomal degradation of YBX3 (Y-box binding protein 3). Under normal conditions, YBX3 promotes the degradation of SLC7A11 (solute carrier family 7 member 11). However, USP5 facilitates the degradation of YBX3, leading to the stabilization of SLC7A11 and thereby promoting CRC cell survival and tumor progression. In patient-derived organoid and xenograft models, USP5 knockout significantly increased the sensitivity of cancer cells to ferroptosis and inhibited tumor growth. Moreover, additional knockout of YBX3 restored the stability of SLC7A11, highlighting the complex regulatory network between USP5, YBX3, and SLC7A11. Systematic functional assays and mechanistic studies further confirmed that the USP5/YBX3/SLC7A11 axis is a central pathway for ferroptosis resistance in CRC. These findings provide novel insights into therapeutic strategies for CRC, especially ferroptosis-based treatments.

Osimertinib resistance is the main challenge in treating EGFR-mutant lung adenocarcinoma (LUAD). The role of N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) in osimertinib-resistant LUAD remains largely unknown. We used MeRIP-seq and circRNA-seq to screen for potential circRNA candidates that influence osimertinib resistance. It was observed that circRNA LMNB1 (cLMNB1) increased the sensitivity of LUAD to osimertinib in vitro and in vivo. Mechanistically, cLMNB1 acts as a scaffold between fibroblast growth factor receptor 4 (FGFR4) and E3 ubiquitin-protein ligase CBL (c-Cbl), enhancing the ubiquitin-dependent degradation of FGFR4. Furthermore, METTL3 and YTHDF2 are responsible for increased m6A modification levels and decreased cLMNB1 expression in osimertinib-resistant LUAD without affecting its functions. Our findings demonstrate that cLMNB1, mediated by m6A modification, overcomes osimertinib resistance by destabilizing the FGFR4 protein in LUAD. cLMNB1 with an m6A modification site mutation (cLMNB1-mut) could be a promising nucleic acid drug, as it has shown excellent efficacy in osimertinib-resistant preclinical models of LUAD.

The TGF-β signaling pathway is initiated when the type II receptor phosphorylates the type I receptor (ALK5) upon TGF-β binding. While E3 ubiquitin ligases regulate TGF-β receptor degradation, their role in modulating receptor catalytic activity via ubiquitination remains largely unexplored. Here, we demonstrate that the E3 ubiquitin ligase MARCH2 enhances ALK5 catalytic activity by conjugating K63-linked ubiquitin chains to lysines 342/343 (K342/343), primarily at endosomes following TGF-β-induced endocytosis. Mutations of ALK5 at K342/343 (K342/343R) abolish its catalytic activity for SMAD2 phosphorylation, leading to impaired TGF-β responses and reduced cell migration in A549 cells. In a mouse model, expression of the ALK5 K342/343 R mutant significantly decreases lung metastasis compared to wild-type ALK5. TCGA analysis further revealed a strong positive correlation between MARCH2 expression and TGF-β target gene expression. Collectively, these findings establish ALK5 ubiquitination at K342/343 by MARCH2 as a crucial regulatory mechanism for ALK5 catalytic activity, TGF-β signaling, and metastasis.

Oral squamous cell carcinoma (OSCC) is an aggressive cancer with limited improvement in patient outcomes despite advances in surgery, chemotherapy, and radiotherapy. The LIM-only protein LMO4 functions as a transcriptional co-regulator and is known to be increased in several epithelial cancers, but its contribution to OSCC has not been well defined. In this study, we found that LMO4 expression was markedly higher in OSCC tissues and was associated with poorer overall survival. Cellular experiments showed that LMO4 enhanced OSCC cell proliferation, migration, and resistance to ferroptosis by promoting the ubiquitin-proteasome-dependent degradation of the tumor suppressor RAB17. Restoration of RAB17 expression reduced these malignant behaviors. In a nude mouse xenograft model, tumors with high LMO4 grew faster and displayed lower RAB17 protein levels. Taken together, our results indicate that LMO4 contributes to OSCC progression through post-translational regulation of RAB17 and ferroptosis control, suggesting that this pathway could serve as a new therapeutic target.

Thioredoxin-Interacting Protein (TXNIP) is an arrestin at the crossroad of redox and glycolytic metabolisms. Prostate cancer (PCa) exhibits a unique metabolic profile due to the glycolytic nature of healthy prostate tissue. We hypothesize that TXNIP plays a pivotal role in the progression of PCa to castration-resistant prostate cancer (CRPC), an incurable stage of the disease characterized by profound metabolic reprogramming and independence from androgens. Only a subset of patients progresses to CRPC, and current stratification tools lack robust biomarkers. TXNIP expression is directly suppressed by androgens and diminishes during tumor initiation and progression, as demonstrated in both human samples and a prostate adenocarcinoma mouse model (TRAMP). TXNIP regulates glucose metabolism by sequestering the glucose transporter GLUT1 away from the membrane, shifting metabolism from glycolysis to glutaminolysis. Nuclear-localized TXNIP induces cell cycle arrest through the upregulation of p27kip1 which is downregulated together with TXNIP in CRPC. The response to androgen deprivation therapy (ADT) strongly depends on TXNIP expression. In the murine model, TXNIP levels were significantly higher in ADT responders compared to non-responders. Furthermore, TRAMP-Txnip-/- prostate tumors exhibited a poorer response to ADT, with increased Ki67 and enhanced viability. In clinical samples, all patients on relapse showed low levels of TXNIP and progressed to CRPC. Our findings identify TXNIP as a critical regulator of cell cycle and glucose metabolism in PCa and emphasize for the first time its essential role in mediating therapeutic responses to ADT.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating the identification of novel therapeutic targets. Here, we identify mitotic spindle organizing protein 2B (MZT2B) as a critical oncogenic driver and potential therapeutic vulnerability in NSCLC. TCGA analysis revealed significant MZT2B upregulation in NSCLC tissues, correlating with adverse clinicopathological features and poor prognosis of patients. Single-cell RNA sequencing analysis confirmed predominant MZT2B enrichment within malignant epithelial cells, particularly in proliferating carcinoma subsets, across primary tumors and metastatic sites (brain, lymph node, pleural effusions). Functional enrichment analyses highlighted MZT2B's association with pathways critical for cellular respiration and mitochondrial ATP synthesis, coupled electron transport. Experimental validation in human NSCLC clinical specimens and various cell types further confirmed consistent MZT2B overexpression. Genetic silencing (via shRNA) or CRISPR/Cas9-mediated knockout of MZT2B in various NSCLC cell types significantly impeded cell viability, proliferation, migration, and invasion, inducing G1-S phase cell cycle arrest, and activating the intrinsic apoptotic pathway. Conversely, MZT2B overexpression promoted aggressive malignant phenotypes of NSCLC cells. Further investigation demonstrated MZT2B's criticality for mitochondrial respiration and overall function, and its silencing or knockout inhibited oxygen consumption rates, ATP production, mitochondrial membrane potential, and cellular redox homeostasis (ROS, GSH/GSSG ratio). Integrated bioinformatic and experimental approaches identified cytochrome c oxidase subunit 5B (COX5B) as a significant downstream effector regulated by MZT2B in NSCLC cells. Restoring COX5B expression or increasing glucose concentration attenuated MZT2B depletion-induced anti-NSCLC cell effects. In vivo studies using subcutaneous xenograft models confirmed that MZT2B knockdown markedly impaired NSCLC tumor growth, reduced proliferation, increased apoptosis, downregulated COX5B expression and diminished mitochondrial function. Collectively, these findings establish MZT2B as a consistently upregulated gene in NSCLC correlating with adverse clinicopathological features and poor prognosis. MZT2B critically regulates mitochondrial function and promotes NSCLC progression, at least partially, through promoting COX5B expression.

Most pancreatic cancer patients exhibit inherent resistance to radiation therapy, and the molecular mechanisms remain poorly understood. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a key ATP-producing glycolytic enzyme, plays a critical role in pancreatic ductal adenocarcinoma (PDAC) radioresistance. In response to ionizing radiation (IR), casein kinase 2 (CK2) is activated and phosphorylates PGK1 at S256. Phosphorylated PGK1 interacts with microrchidia CW-type zinc finger 2 (MORC2). Importantly, PGK1 functions as a protein kinase and phosphorylates MORC2 at S711, thereby enhancing the DNA-dependent ATPase activity of MORC2 to facilitate chromatin remodeling and DNA repair. Disruption of CK2-mediated PGK1 phosphorylation or PGK1-dependent MORC2 phosphorylation sensitizes PDAC cells and mouse tumors to IR. Clinically, the levels of PGK1 pS256 and MORC2 pS711, which are mutually correlated, are positively associated with poor survival in radiotherapy-treated PDAC specimens. These findings highlight the critical role of the nonmetabolic functions of PGK1 in DNA damage repair and PDAC radioresistance.