Nanoplastics (NPs) have emerged as pervasive environmental contaminants, yet their role in colorectal cancer (CRC) pathogenesis remains poorly understood. Here, we demonstrate that chronic oral exposure to polystyrene nanoplastics (PS-NPs) promotes colorectal tumorigenesis in a murine azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC model through disruption of the gut microbiota–metabolite–immune axis. Mechanistically, PS-NPs accumulate predominantly in the colon and cause structural damage to intestinal epithelial microvilli. PS-NPs induce gut microbiota dysbiosis characterized by depletion of the beneficial bacterium Faecalibaculum rodentium (F. rodentium) and a consequent reduction in its protective metabolite, propionic acid. This metabolic perturbation attenuates Th17 cell differentiation and IL-17 A production, thereby impairing anti-tumor immunity. Clinically, we detected diverse microplastics in CRC patient tissues and blood. Collectively, our multi-omics and functional analyses delineate a mechanistic pathway linking environmental NPs exposure to colorectal carcinogenesis via the F. rodentium–propionic acid–Th17 cell axis, highlighting the gut microbiome and its metabolites as potential targets for intervention against pollution-associated cancer risks.
Metabolic reprogramming is a defining feature of hepatocellular carcinoma (HCC), enabling malignant cells to sustain proliferation, adapt to nutrient and oxygen limitation, evade antitumor immunity, and survive therapeutic stress. Emerging evidence indicates that RNA modification networks provide an important interface between metabolic states and post-transcriptional gene regulation. RNA modifications and their associated writers, erasers, and readers can reshape glucose, lipid, and amino acid metabolism by regulating RNA stability, translation, processing, and RNA–protein interactions. Conversely, nutrient availability, glycolytic activity, and metabolites such as lactate, acetyl-CoA, and S-adenosylmethionine can influence RNA-modifying enzymes, modification abundance, reader activity, and RNA fate, thereby establishing reciprocal metabolic–RNA regulatory circuits. Importantly, however, the functions of RNA-modification-associated proteins are not invariably modification-dependent; several regulators also exert catalytic-independent or non-canonical effects through protein interactions, chromatin regulation, or metabolic signaling. Distinguishing these mechanisms is therefore essential for defining genuine epitranscriptomic regulation. These reciprocal networks extend beyond tumor-cell-autonomous metabolism to influence redox homeostasis, ferroptosis and cuproptosis, cancer stemness, tumor immunity, and therapeutic resistance. Long non-coding RNAs and circular RNAs further intersect with RNA modification machinery as regulators, scaffolds, and, in some contexts, modification substrates, adding another layer of metabolic plasticity. Here, we critically discuss how major RNA modifications, with particular emphasis on m⁶A and the emerging but less extensively characterized roles of m⁵C, m⁷G, ac⁴C, and other modifications, interface with glucose, lipid, and amino acid metabolism in HCC. We further examine how metabolic remodeling feeds back on RNA-modification machinery and modification-dependent RNA regulation, while distinguishing these effects from modification-independent functions of the same regulators. Non-coding RNA crosstalk, tumor immunometabolism, regulated cell death, and therapeutic adaptation are also integrated into this framework. Finally, we evaluate therapeutic strategies targeting RNA-modification machinery or downstream metabolic dependencies in combination with targeted therapy, chemotherapy, ferroptosis or cuproptosis induction, and immune checkpoint blockade. We highlight persistent challenges, including uneven mechanistic evidence across RNA modification classes, limited site-specific causal validation, insufficient metabolic-flux measurements, catalytic-independent functions of modification-associated proteins, and unresolved cell-type and spatial heterogeneity. A more rigorous distinction between RNA modification-dependent and modification-independent mechanisms will be critical for identifying context-specific vulnerabilities and translating metabolic–RNA regulatory networks into biomarker-guided precision therapy for HCC.
Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N 6-methyladenosine (m6A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m6A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m6A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m6A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m6A modification of ZBTB7A facilitated recognition by the m6A reader YTHDF1/3 complex, enhancing its translation and expression. This m6A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m6A erasure (TRME) system to achieve site-specific demethylation at a single site (m6A_site_411666) within ZBTB7A mRNA, without perturbing m6A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of CRLM.
Genomic integrity requires precise chromosome replication and segregation during the cell cycle. Disruptions in this process drive chromosomal instability (CIN), a key factor in tumor evolution and therapeutic resistance. Traditionally, MAD genes, including MAD1L1 and MAD2L1, were categorized as spindle assembly checkpoint components, whereas MAD2L2 was primarily recognized as a DNA repair protein. Increasingly, these genes are recognized as part of an integrated genome surveillance system, driven by shared structures, conformational dynamics, and interconnected regulatory mechanisms. Accordingly, the review redefines the MAD gene family as a coordinated axis for genomic stability, governed by conserved HORMA domains. The unique structural features, conformational plasticity, and protein–protein interaction interfaces of MAD-family proteins present unexplored therapeutic opportunities. Understanding these properties and their interaction networks may reveal cancer-specific vulnerabilities and facilitate the development of selective therapeutic strategies, including approaches to overcome therapeutic resistance, particularly in cancers characterized by high chromosomal instability. The MAD family is presented as a unified regulatory node that bridges mitosis and DNA damage response, rather than isolated proteins. A conserved HORMA-domain framework enables coordinated conformational signaling across MAD1L1, MAD2L1, and MAD2L2. Distinct MAD-family dysregulations generate mechanically different chromosomal instability states in cancer. Indirect targeting of MAD-associated pathways reveals actionable vulnerabilities in CIN-driven cancers. MAD-family–based stratification may enable precision targeting of checkpoint- versus repair-dependent tumors.
Copper is an essential redox cofactor required for mitochondrial respiration and antioxidant defense, yet its dysregulation creates a therapeutic vulnerability that can be exploited by copper active agents. Elesclomol and neocuproine are two potent copper active compounds, but whether they induce the same form of cuproptosis, a copper-dependent cell death mechanism, has remained unclear. We aimed to elucidate the cytotoxic programs triggered by these two agents and to determine whether distinct mechanistic forms of cuproptosis exist. Our study integrates limited-proteolysis proteomics to identify compound-responsive changes in protein structural accessibility, whole-genome CRISPRa (activation) screening, transcriptomic analysis of 436 CCLE cancer cell lines, mass spectrometry-based analysis of cellular and tumor copper abundance, genetic perturbation studies, mitochondrial functional assays, and mitophagy analyses. Pathway enrichment and functional validation were used to identify adaptive survival programs and compound-specific copper-handling mechanisms. Building on the previously established FDX1-dependent cuproptosis mechanism induced by elesclomol, we designate this pathway as canonical cuproptosis (c-CPX) and identify neocuproine as inducing a mechanistically distinct, FDX1-independent form of cuproptosis, which we term non-canonical cuproptosis (nc-CPX). In c-CPX, FDX1 mediates elesclomol delivered Cu(II) to Cu(I) reduction, leading to rapid oligomerization of lipoylated mitochondrial proteins and subsequent proteotoxic stress. In contrast, neocuproine induces n-CPX, a FDX1-independent copper-dependent death program that preferentially engages neocuproine stabilized Cu(I)-handling and stress-adaptation networks. Despite its FDX1 independence, neocuproine rapidly induces oligomerization of lipoylated DLAT, identifying an early point of convergence with canonical cuproptosis. Large-scale analysis of CCLE cancer cell lines further revealed that sensitivity to both neocuproine and elesclomol is associated with enrichment of oxidative phosphorylation (OXPHOS) transcriptional programs. Notably, neocuproine-sensitive cancer cells additionally displayed significantly higher mesenchymal/EMT scores across multiple independent gene-expression signatures, linking an OXPHOS-enriched, mesenchymal cell state to increased susceptibility to neocuproine-induced copper-dependent cell death. Limited-proteolysis profiling identified ATOX1 among the prominent neocuproine-responsive proteins. Functional validation demonstrated that ATOX1 depletion partially attenuates neocuproine-induced cytotoxicity, but not elesclomol toxicity, while ATOX1 loss itself promotes DLAT oligomerization, supporting a specific contribution of ATOX1-dependent Cu(I) handling to nc-CPX. CRISPRa screening further revealed that adaptive programs enriched during neocuproine exposure predominantly involve proteasomal and lysosomal pathways; whereas elesclomol is associated with distinct signaling and bioenergetic programs, including PI3K, JAK–STAT, and MAPK pathways, as well as oxidative phosphorylation and glutathione metabolism. The functional relevance of the neocuproine-associated pathways was supported by enhanced cytotoxicity upon pharmacological inhibition of proteasomal or lysosomal function. Despite their divergent initiation mechanisms, both canonical and non-canonical cuproptosis converge on early oligomerization of lipoylated mitochondrial proteins followed by Fe–S-protein loss, respiratory-chain dysfunction, mitochondrial remodeling, impaired mitochondrial quality control, and respiratory failure. Both compounds also induce cytoplasmic and mitochondrial ROS and late apoptotic features. Continuous N-acetylcysteine (NAC) exposure reduced the labile intracellular Cu(I) signal and rescued cytotoxicity; whereas NAC pretreatment followed by washout did not protect against subsequent neocuproine or elesclomol exposure. Together with the lack of rescue by caspase inhibition and the delayed appearance of apoptotic features, these findings support ROS accumulation and apoptosis as predominantly downstream consequences rather than defining initiating mechanisms. Our findings establish a mechanistic framework distinguishing canonical FDX1 dependent cuproptosis from non-canonical FDX1 independent cuproptosis. Rather than representing separate downstream death programs, c-CPX and nc-CPX constitute distinct upstream copper-handling routes that converge on a shared mitochondria-centered proteotoxic program. These results provide insight into copper-driven cytotoxicity and suggest FDX1 dependency, ATOX1-dependent copper-handling, EMT/OXPHOS state, and proteostasis pathways as candidate biomarkers and therapeutic vulnerabilities for further investigation.
