Biology subjects

Hou, Z.

Publications and source records attributed to Hou, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Cooperative IDR-folded domain interplay governs HP1α phase separation and underlies biphasic regulation by pathogenic poly-PR

HP1 undergoes liquid-liquid phase separation (LLPS), yet the prevailing model, which attributes condensation almost entirely to intrinsically disordered regions (IDRs), leaves the role of its folded domains unresolved. Using solution and solid-state NMR, we show that HP1 LLPS is instead governed by reciprocal interplay between IDRs and folded domains. Within the condensed phase, solid-state NMR reveals a dynamic hierarchy: the chromoshadow domain (CSD) assembles into polymorphic oligomers that form rigid cores, while the phosphorylation sites on the N-terminal extension (NTE) remain highly mobile, challenging their proposed role as stable multivalent hubs. Phosphorylation of the NTE instead promotes LLPS primarily by increasing local rigidity and releasing the NTE from the chromodomain (CD) to relieve autoinhibition, with electrostatic charge contributing secondarily. The C-terminal extension (CTE) suppresses phase separation through two routes: weakening the association between the hinge region (HR) and the CSD, and inhibiting interactions between CSD dimers. ALS-associated poly-PR targets this network at the NTE and exerts concentration-dependent biphasic regulation, promoting LLPS at low concentrations via multivalent bridging and dissolving condensates at high concentrations via saturation, a switch recapitulated in cells and in mouse brain. These findings reframe HP1 condensation from an IDR-driven process to one cooperatively governed by IDR-folded domain interplay.

biochemistry↗

bioRxiv2026

In-cell structural analysis reveals a distinctive chloroplast ribosome in Chlamydomonas reinhardtii

Chloroplast ribosomes synthesize plastid-encoded components of photosynthetic machinery, yet their structure and organization remain poorly understood. We combined cryo-focused ion beam milling, cryo-electron tomography and subtomogram averaging to determine native chloroplast ribosomes in Chlamydomonas reinhardtii. The 4.4-4.9 [A] structure revealed a large arch-like extension on the small subunit (SSU). Comparisons with bacterial and plant chloroplast ribosomes, supported by proteomics, AlphaFold3 predictions and a recent atomic model, indicate that the arch is formed by insertions and extensions in SSU proteins. Classification resolved active, thylakoid-associated ribosomes with density adjacent to the nascent peptide exit and an arch-moved state enriched among thylakoid-associated particles, with coordinated displacement of the arch and beak. Phylogenetic analysis revealed an evolutionary mosaic: the uS3c insertion is broadly distributed across Chlorophyceae, whereas the uS2c insertion, uS5c and PSRP7 are concentrated in Chlamydomonadales, with PSRP7 also in Sphaeropleales. Nuclear-encoded components were recruited stepwise onto a plastid-encoded scaffold, with all four under comparable purifying selection. These findings link a lineage-specific SSU extension to ribosome dynamics, thylakoid association and evolution, highlighting the value of in-cell structural analysis.

plant biology↗

bioRxiv2026

Single-cell profiling reveals MMP7-associated epithelial transition and immune-stromal remodeling in esophageal carcinogenesis

The progression from reflux esophagitis (RE) to Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) is a major route of inflammation-associated esophageal tumorigenesis, but the cellular transitions involved remain incompletely understood. We performed single-cell transcriptomic profiling of RE, BE, and EAC tissues and integrated public EAC datasets, yielding 51,283 cells across the RE-BE-EAC continuum. The analysis identified stage-associated epithelial and microenvironmental differences. Pseudotime analysis placed Basal epithelial cells along two differentiation branches, one toward mature epithelial states and the other through proliferative and gastric-type metaplastic states toward copy number alteration-bearing malignant epithelial cells. MMP7 increased along this malignant branch, was enriched in cancer-associated epithelial cells. Its knockdown reduced the proliferation and migration of OE19 and OE33 cells, supporting an association with proliferative and migratory phenotypes. In parallel, the microenvironment shifted toward immune suppression and stromal remodeling, with increased T-cell exhaustion, macrophage polarization toward tumor-associated states, and enrichment of CAF-like myofibroblasts. Ligand-receptor analysis further suggested an epithelial-centered communication network involving MDK-SDC2/LRP1/NCL interactions between malignant epithelial cells and fibroblast, T-cell, and myeloid compartments. These results identify MMP7-associated epithelial states and candidate MDK-related communication pathways for further longitudinal and functional validation.

cancer biology↗

bioRxiv2026

Foundation Model RNAGAN Enhances Biomedical Insight of Nasopharyngeal Carcinoma Metastasis

RNAGAN (version 2.0, https://github.com/ZhaozhengHou-HKU/RNAGAN-2.0.git) is a published foundation model that analyzes single-cell and bulk-level RNA sequencing samples and enables multiple applications that enhance medical insights. Here we applied this model to Nasopharyngeal Carcinoma (NPC) as in-context few-short format (i.e., the model was never trained with any NPC data). We conducted all four supported functions, which include sample stratification, vectorization, pseudo data generation, and marker identification. The results were then used for identifying metastatic NPC and to investigate mechanisms associated with NPC metastasis. Examination with stratification showed that the accuracy of RNAGAN results for evaluating the metastasis risk in NPC patients are comparable to or outcompeted recently published risk estimation linear prediction model. Vectorization results present consistency across multiple cohorts and RNAGAN model versions. In the task of identifying markers and mechanisms related to NPC metastasis, incorporating pseudo data substantially enhanced the representativeness of single-cohort-based differential expression (DE) analysis. Moreover, RNAGAN identified metastasis-related marker genes based on single cohort, were concordant with the ground truth obtained across multiple cohorts (p=1.05e-9). Regarding biomedical mechanisms, RNAGAN enabled second-order feature extraction, unveiling a remarkable domination of the protective function of adaptive immune responses (as indicated by IL21R levels) over the hazardous function of chronic, non-resolving innate inflammation (as indicated by S100A8 levels) against NPC metastasis after first-line treatment. This association demonstrates a high degree of consistency with the external cohort. This study demonstrates the utility of the foundation model RNAGAN in uncovering therapeutic insights for novel cancer types without extra training. We reveal a critical spatial mechanism preventing distant metastasis via humoral anti-tumor immunity in NPC. High S100A8 expression by innate antigen-presenting cells (APCs) triggers an inflammatory cascade promoting epithelial-mesenchymal transition (EMT) and metastasis. However, when germinal center IL21R+ B cells simultaneously colocalize with these innate signals, they override this suppressive tissue stress. Spatial analysis shows that a high S100A8/IL21R intersection within tumor regions strictly distinguishes treatment responders, whereas non-responders display spatial mismatch or S100A8+ hyper-infiltration. This coordinated innate-adaptive cross-talk sustains functional tertiary lymphoid structures (TLS) that mature IgG-secreting plasma cells, which opsonize and eliminate emerging EMT tumor cells before systemic escape. Consequently, while S100A8 alone is an unreliable prognosticator, its spatial colocalization with IL21R is a robust protective indicator overlooked by conventional bulk analysis methods.

cancer biology↗

bioRxiv2026

Spatiotemporal biogenesis of thylakoid membranes in the green alga Chlamydomonas reinhardtii

Thylakoid membranes are essential for oxygenic photosynthesis, yet the mechanisms underlying their spatial and temporal biogenesis remain poorly understood. Here, using a light-induced membrane regeneration system in Chlamydomonas reinhardtii, we generate a time-resolved map of thylakoid formation and photosynthetic complex assembly at unprecedented spatial and temporal resolution by integrating super-resolution fluorescence microscopy, cryo-electron tomography, proteomics, and spectroscopy. We show that thylakoid biogenesis is globally distributed and multipolar, with new membrane formation occurring at multiple sites across the chloroplast, including regions adjacent to the inner envelope membranes in both basal and lobe regions. We identify F-ATP synthase storage membranes and map the redistribution of translating ribosomes from T-zone enrichment to a chloroplast-wide distribution at early stages of thylakoid formation, consistent with decentralized synthesis of photosynthetic complexes. We further delineate the hierarchical assembly of photosystem supercomplexes, starting with formation of reaction centers. Together, these findings refine the spatial organization of photosynthetic membrane biogenesis and establish a unified spatiotemporal framework linking thylakoid formation, translational activation, and functional maturation, providing a mechanistic basis for plastid engineering to enhance photosynthetic efficiency.

Cell Biology↗

bioRxiv2026

Functionally dark genes and the transcriptomic landscape of sporulation in a model mushroom-forming fungus

Spores are the primary means of fungal reproduction, contributing to genetic diversity, colonization, and adaptation. Although spore formation is a pivotal part of the fungal life cycle, its genetic underpinnings remain poorly known. In this study, we characterize transcriptomic changes from late meiosis to early basidiospore formation in the mushroom-forming fungus Coprinopsis cinerea, decipher several cellular processes, and identify novel genes involved in this process. We identify distinct trajectories of gene expression, each of which display different functional signals, corresponding to meiotic and morphogenetic processes and transitions between these. Our analyses identify diverse arrays of fungal cell wall modifying carbohydrate-active enzymes, ferritins, a putative catechol-melanin synthesis pathway, as well as components of the mitotic/meiotic apparatus. We present twelve highly conserved genes with roles specific to sexual sporulation in both budding yeast and C. cinerea, indicating deep conservation of the gene networks driving sexual spore formation. Reverse genetics identified three conserved but functionally poorly characterized genes conferring sporeless and spore-poor phenotypes that result from postmeiotic developmental arrests stemming from spore inflation and nuclear migration problems. Overall, this study provides novel insight into basidiomycete spore formation and highlights the cornucopia of novel functions encoded by functionally dark genes.

microbiology↗

bioRxiv2026

Multi-omic responses to acute exercise in abdominal subcutaneous adipose tissue of sedentary adults: findings from MoTrPAC

Exercise induces widespread health benefits across multiple tissues, yet the acute molecular responses in human adipose tissue remain poorly defined. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled temporal molecular changes in abdominal subcutaneous adipose tissue (ASAT) following a single bout of exercise. Healthy sedentary adults were randomized to endurance (EE), resistance (RE), or control (CON) groups. ASAT biopsies were collected pre-exercise and at 45min, 4hr, and 24hr post-exercise, followed by transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses. EE and RE elicited distinct, time-resolved molecular programs involving angiogenesis, extracellular matrix remodeling, mitochondrial metabolism, substrate utilization, and circadian regulation. Phosphoproteomics revealed acute changes in cytoskeletal and branched-chain amino acid metabolism proteins associated with glycemic control. Temporal metabolomic shifts were cell-type-specific. Finally, we identified candidate adipose-derived exerkines with predicted endocrine actions. This multi-omic map of acute ASAT responses offers insight into adipose-specific mechanisms by which exercise promotes metabolic health.

systems biology↗

bioRxiv2025

In situ chromatin dynamics and HIV-1 nuclear trafficking

The organization and dynamics of chromatin within intact nuclei remain poorly defined, limiting understanding of how nuclear architecture influences macromolecular transport. HIV-1 provides a striking example of a large complex that must traverse this dynamic landscape to access integration sites within transcriptionally active regions. Here, we combine a functional nuclear import system with correlative cryo-electron tomography to visualize chromatin architecture and HIV-1 cores in situ during nuclear penetration. Native nucleosomes resolved at 5.6 [A] reveal four structural classes, from compact conformations at the nuclear periphery to open, flexible forms in the interior, defining a spatially heterogeneous and dynamic chromatin landscape. Within this environment, HIV-1 cores decorated with nuclear factors exclude nearby nucleosomes and preferentially associate with open chromatin. Disruption of CPSF6-capsid interactions abolishes these associations, confining viral cores to peripheral chromatin. These findings establish an in situ framework linking chromatin structure and dynamics to HIV-1 nuclear trafficking and provide a structural basis for viral navigation within the dynamic nuclear landscape.

microbiology↗

bioRxiv2025

Functional characterization of a Con7-related transcription factor in Coprinopsis cinerea indicates evolutionary conservation of morphogenetic roles

Fruiting bodies of mushroom-forming fungi (Agaricomycetes) exhibit the highest degree of multicellular complexity in fungi, yet the molecular underpinnings of their developmental programs remain incompletely understood. Here, we characterize gcd1, a gene encoding a transcription factor in the Con7 subfamily of C2H2-type zinc finger proteins. This subfamily has previously been implicated in pathogenic morphogenesis in Ascomycota, but their role in Agaricomycetes has not previously been addressed. In Coprinopsis cinerea, CRISPR/Cas9-mediated deletion of gcd1 resulted in strains with severely impaired fruiting body morphogenesis, with malformed cap, stipe, and gill tissues. Gcd1 deletion strains lacked universal veil, resembling species with open (gymnocarpous) development. We find that GCD1/Con7 homologs are widely distributed in most Dikarya species and are mostly encoded by a single gene in each species genome. Transcriptome analyses identified several misregulated genes in the {Delta}gcd1 mutant, which pinpoint potential mechanisms underlying its developmental defects as well as provided insights into the morphogenesis of mushroom fruiting bodies. These findings establish GCD1 as a key regulator of multicellular development in C. cinerea and broaden the known functions of Con7-like transcription factors to include fruiting body morphogenesis in Agaricomycetes. Overall, our results and the morphogenetic role of Con7-like transcription factors of Ascomycota suggest functional conservation over half a billion years of evolution.

microbiology↗

bioRxiv2025

DeepPGDB: A Novel Paradigm for AI-Guided Interactive Plant Genomic Database

DeepPGDB (https://www.deeppgdb.chat) is the first AI-driven plant genomics database designed to lower technical barriers in multi-omics research by enabling natural language-based data access and analysis. Integrating over 50 high-quality plant genomes, DeepPGDB combines fine-tuned large language models (LLMs) with prompt engineering to interpret user queries, generate standardized bioinformatics commands, and retrieve or visualize genomic data. Key functionalities include sequence retrieval, BLAST alignment, gene localization, expression profiling, and population genetics analysis, all presented via an intuitive conversational interface. A summarization module further enhances biological reasoning, inferring insights such as haplotype differentiation or protein properties. Benchmarking revealed that Deepseek-r1:14b optimized for short pre-prompts delivers high accuracy and speed. By bridging computational and biological expertise, DeepPGDB democratizes genomic research, fostering interdisciplinary collaboration and accelerating discoveries in agriculture and biotechnology.

bioinformatics↗

bioRxiv2025

Endurance exercise drives temporal and sexual dimorphic multi-omic adaptations in liver metabolism-Findings from MoTrPAC.

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

physiology↗

bioRxiv2025

Kinship estimation bias carries over to heritability estimation bias using variance components

Heritability is a fundamental parameter of diseases and other traits, quantifying the contribution of genetics to that trait. Kinship matrices, also known as Genetic Relatedness Matrices or "GRMs", are required for heritability estimation with variance components models. However, the most common "standard" kinship estimator employed by GCTA and other approaches, can be severely biased in structured populations. In this study, we characterize heritability estimation biases in GCTA due to kinship estimation biases under population structure. For the standard ratio-of-means (ROM) kinship estimator, we derive a closed-form expression for heritability bias given by the mean kinship value and the true heritability. The standard mean-of-ratios (MOR) estimator is the most widely used in practice, and exhibits more severe bias than ROM due to upweighing low-frequency variants. Using simulation studies with admixture and family structures, as well as simulated traits from 1000 Genomes genotypes, we find that only Popkin, which is the only unbiased population kinship estimator, produces unbiased heritability estimates in structured settings. Pedigree-only estimates have upward heritability biases when there is population structure. Finally, we analyze three structured datasets with real phenotypes--the San Antonio Family Study, the Hispanic Community Health Study / Study of Latinos, and a multiethnic Nephrotic Syndrome cohort. The standard MOR estimator can produce both downward and upward heritability biases depending on population structure and variant frequency spectrum, compared to the other two estimators. Overall, common kinship estimators result in heritability estimation biases when applied to structured populations, a challenge that Popkin successfully overcomes.

genetics↗

bioRxiv2025

Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish the upregulation of the one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy. Statement of SignificanceUsing both genetic and pharmacologic approaches, this study identifies Ewing sarcomas dependence on the mitochondrial arm, but not the cytoplasmic arm, of one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.

cancer biology↗

bioRxiv2025

Correlative In Situ Cryo-ET Reveals Cellular and Viral Remodeling Associated with Selective HIV-1 Core Nuclear Import

Lentiviruses like HIV-1 infect non-dividing cells by traversing the nuclear pore, but studying this process has been challenging due to its scarcity and dynamic nature in infected cells. Here, we developed a robust cell-permeabilization system that recapitulates HIV-1 nuclear import and established an integrated cryo-correlative workflow combining cryo-CLEM, cryo-FIB, and cryo-ET for targeted imaging of this process. These advancements enabled the successful capture of 1,899 HIV-1 cores at various stages of nuclear import. Statistical and structural analyses of native wild-type and mutant cores revealed that HIV-1 nuclear import depends on both capsid elasticity and nuclear pore adaptability, as well as nuclear factors such as CPSF6. Brittle cores fail to enter the nuclear pore complex (NPC), while CPSF6-binding-deficient cores stall inside the NPC, resulting in impaired nuclear import. Intriguingly, nuclear pores function as selective filters favoring the import of smaller, tube-shaped cores. Our study opens new avenues for dissecting the biochemistry and structural biology of HIV-1 nuclear import as well as downstream events including core uncoating and potentially integration, with unprecedented detail.

microbiology↗

bioRxiv2025

In-cell Structure and Variability of Pyrenoid Rubisco

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is a key enzyme in the global carbon cycle, catalyzing CO2 fixation during photosynthesis. To overcome Rubiscos inherent catalytic inefficiency, many photosynthetic organisms have evolved CO2-concentrating mechanisms. Central to these mechanisms is the pyrenoid, a protein-dense organelle within the chloroplast of eukaryotic algae, which increases the local concentration of CO2 around Rubisco and thereby enhances its catalytic efficiency. Although the structure of Rubisco has been extensively studied by in vitro methods such as X-ray crystallography and single particle cryo-EM, its native structure within the pyrenoid, its dynamics, and its association with binding partners remain elusive. Here, we investigate the structure of native pyrenoid Rubisco inside the green alga Chlamydomonas reinhardtii by applying cryo-electron tomography (cryo-ET) on cryo-focused ion beam (cryo-FIB) milled cells, followed by subtomogram averaging and 3D classification. Reconstruction at sub-nanometer resolution allowed accurate modeling and determination of a closed (activated) Rubisco conformation. Comparison to other reconstructed subsets revealed local variations at the complex active site and at the large subunit dimers interface, as well as association with binding proteins. The different structural subsets distribute stochastically within the pyrenoid. Taken together, these findings offer a comprehensive description of the structure, dynamics, and functional organization of Rubisco within the pyrenoid, providing valuable insights into its critical role in CO2 fixation.

cell biology↗

bioRxiv2024

Metagenomic mining reveals novel viral histones in dsDNA viruses

The compaction of genomic DNA into nucleosomes with the help of histones had long been considered as a fundamental feature exclusive to eukaryotic cells. However, it was recently shown that archaea and bacteria also encode histones. A complex picture has emerged with more recent discoveries of eukaryotic-like histones within one phylum of double-stranded DNA (dsDNA) viruses. Nevertheless, the extent to which other dsDNA viruses encode histones remains largely unexplored. Here we conducted a metagenomic survey of viral histones that were further clustered based on sequence and predicted structural similarities. We identified over 1,500 viral histones and histone-fold proteins, including previously undescribed proteins found in the viral class Caudoviricetes. Structural predictions and in vitro assays demonstrated that histone triplets (where three histone folds are fused) and singlets co-occurring in the same viral genome are capable of forming nucleosome-like particles. Beyond nucleosomal histone functions, our analysis revealed six types of structurally and functionally diverse viral histone-fold proteins, some of which do not have known structural or functional homologs. Altogether, our findings reveal a previously unrecognized diversity of viral histones in dsDNA viruses, expanding the known repertoire, structural diversity, and functional versatility of viral histones beyond nucleocytoplasmic large DNA viruses. HighlightsO_LIHistone triplets and singlets co-occurring in the same dsDNA viral genomes assemble into nucleosome-like particles C_LIO_LISix novel types of structurally and functionally distinct viral histone-fold proteins are identified C_LIO_LIThe presence of viral histones is significantly positively associated with proteins containing SNF2 chromatin remodeling domain found in viral genomes C_LI

microbiology↗

bioRxiv2024

The molecular mechanism of temperature-dependent phase separation of Heat shock factor 1

Heat shock factor 1 (HSF1) is the critical orchestrator for a cell responding to heat shock, and its dysfunction is linked to cancers and neurodegenerative diseases. HSF1 undergoes phase separation upon heat shock, and its activity is regulated by various post-translational modifications (PTMs). Despite its importance, the molecular details underlying HSF1 phase separation, temperature sensing, and post-translational modifications (PTMs) regulation remain poorly understood. Here, we discovered that HSF1 exhibits temperature-dependent phase separation with a lower critical solution temperature (LCST) behavior due to entropy contribution from solvent molecules, providing a new conceptual mechanism accounting for HSF1 activation. We employed a synergistic approach combining coarse-grain simulation and nuclear magnetic resonance spectroscopy to reveal the residue-level molecular details of the interactions driving the phase separation of wild-type HSF1 and its distinct PTM patterns at various temperatures. The identified interaction sites were further validated with biochemistry assays and mapped interface accounts for HSF1 functions reported. Importantly, the amino acid substitution experiment reveals the molecular grammar for temperature-dependent HSF1 phase separation is species-specific and physiologically relevant. These findings delineate chemical code that integrates protein PTM patterns with accurate phase separation for body physiological temperature control in animals.

biochemistry↗

bioRxiv2024

RIPK4 driven by TP53 mutations promotes resistance to redox stress of CRC by phosphorylating MTHFD1

This study investigates advanced colorectal cancer (CRC), focusing on its tendency for distant metastasis and chemotherapy resistance. It highlights the importance of PANoptosis, a cell death pathway, and the role of the Receptor-interacting serine/threonine-protein kinase (RIPK) family in tumor progression. RIPK4s tissue-specific functions in cancer cell behavior are emphasized, including its influence on invasion, migration, and oxidative stress resistance. The study reveals the critical balance of reactive oxygen species (ROS) in cancer cells, linked to antioxidant defenses and NADPH production for survival. A key finding is the connection between TP53 mutations in CRC and increased RIPK4 expression, which enhances MTHFD1 phosphorylation, boosts NADPH production, reduces ROS, and promotes resistance to PANoptosis, leading to metastasis. The research identifies the molecular basis of CRC metastasis, showing how RIPK4 regulates MTHFD1 to resist PANoptosis, offering new therapeutic targets for metastatic CRC and potential improvements in patient outcomes.

molecular biology↗