Abstract Background Oxaliplatin‐related neuropathy (OIPN) remains a frequent chemotherapy‐induced complication, yet its underlying mechanisms remain incompletely understood. Emerging evidence implicates pyroptosis in OIPN pathogenesis, and palmitoylation has been recognised as a critical mechanism in neurological disorders. Objective This investigation set out to examine the part played by the palmitoyltransferase Zdhhc14 in pyroptosis in OIPN as well as to clarify the fundamental molecular processes. Methods A mouse model of OIPN was developed through intraperitoneal oxaliplatin administration, and primary neuronal cultures derived from dorsal root ganglia were exposed to oxaliplatin to simulate OIPN in vitro. Bioinformatics analysis was performed using the GSE255097 dataset. Gene and protein expression were examined by quantitative real‐time PCR, Western blot and immunofluorescence staining. Pyroptosis was assessed by lactate dehydrogenase release, flow cytometry and detection of pyroptosis‐related proteins. Co‐immunoprecipitation, immunoprecipitation and cycloheximide chase assay were applied to evaluate the mechanisms. Results Zdhhc14 was significantly up‐regulated in dorsal root ganglion (DRG) of OIPN mice in a time‐dependent manner. Zdhhc14 deficiency alleviated OIPN phenotypes, including mechanical hyperalgesia and cold allodynia, neuroinflammation and DRG pyroptosis. Mechanistically, Zdhhc14 binds to GBP5 and promotes its modification at Cys12, which is required for Zdhhc14‐mediated suppression of K48‐linked ubiquitination and subsequent proteasomal degradation, thereby stabilising GBP5. GBP5 knockdown phenocopied the protective effects of Zdhhc14 deficiency, whereas GBP5 overexpression reversed these effects. Importantly, mutation of the GBP5 palmitoylation site abolished the pro‐pyroptotic effects of Zdhhc14. Conclusions These findings indicate that the Zdhhc14/GBP5 palmitoylation axis critically regulates DRG pyroptosis and neuroinflammation in OIPN, identifying a novel mechanism and a potential mechanistic target warranting further translational evaluation for this debilitating condition.
Abstract Background Ovarian cancer (OC) remains the most lethal gynaecological malignancy, and acquired resistance to PARP inhibitors such as olaparib represents a major clinical challenge. Although dysregulation of iron metabolism has been implicated in tumorigenesis, the specific role of the iron exporter SLC40A1 (ferroportin, FPN) in mediating olaparib resistance remains poorly understood. The study aimed to elucidate the clinical significance of FPN deficiency and to explore therapeutic strategies for reversing olaparib resistance. Methods FPN expression was evaluated in OC samples from a clinical cohort of 19 patients, stratified by olaparib responsiveness, to determine its prognostic value. Functional mechanisms were investigated using multiple OC cell lines, patient‐derived organoids (PDOs), and mouse xenograft models. We integrated analyses of iron homeostasis, ROS dynamics, DNA repair capacity, and innate immune signaling, with a focus on the cGAS–STING–STAT3 signaling cascade. The therapeutic potential of combining olaparib with the ferroptosis inducer erastin or the STING inhibitor C‐176 was assessed as a strategy to overcome FPN deficiency‐driven resistance. Results Clinically, FPN expression was significantly downregulated in olaparib‐resistant tissues compared with sensitive controls ( p < 0.05), and low FPN levels were strongly associated with poor therapeutic outcomes. Mechanistically, FPN deficiency promoted intracellular iron accumulation and ROS generation, which led to increased ferroptosis vulnerability, impaired homologous recombination repair (HRR) and concomitant activation of the cGAS–STING–STAT3 inflammatory axis, thereby driving olaparib resistance. Notably, in vivo studies demonstrated that combining olaparib with either erastin or C‐176 significantly suppressed tumour growth and restored drug sensitivity compared with monotherapy ( p < 0.01), supporting the translational potential of targeting this axis. Conclusions Our study establishes a clinically relevant mechanistic connection between ferroportin deficiency and cGAS–STING–STAT3‐mediated olaparib resistance in OC. We identify the FPN–ROS–cGAS–STING–STAT3 axis as an actionable vulnerability in resistant OC, indicating that this pathway is a promising therapeutic target to overcome olaparib resistance. Highlights FPN loss drives olaparib resistance and predicts poor outcomes in ovarian cancer. FPN loss causes iron and ROS accumulation, impairing HRR and activating the cGAS–STING–STAT3 axis. The cGAS–STING–STAT3 pro‐survival program drives olaparib resistance. STING inhibition restores olaparib sensitivity in resistant ovarian cancer.
Abstract Background Brain metastasis remains a major cause of mortality and treatment failure in non‐small cell lung cancer (NSCLC). However, current models of cerebral dissemination rarely integrate microbiome‐dependent systemic and intratumoral biology.This Review examines the potential microbiome‐brain metastasis axis linking gut, lung, and intratumoral microbial communities to intracranial dissemination and therapeutic response. Methods A reproducible literature search was conducted to evaluate proposed mechanisms underlying microbiome‐associated brain metastasis. Evidence for each mechanistic claim was graded using a four‐level evidence scheme (E1‐E4), while microbial detection confidence was assessed using a four‐tier hierarchy (D1‐D4). Results No component of the proposed axis reached E1 evidence, and all published microbial observations in NSCLC brain metastasis rests on nucleic‐acid detection alone. Five mechanisms are examined: circulating microbial metabolites acting on endothelial permeability and glial reactivity; microbiome‐imprinted immune‐cell trafficking;intracellular bacteria within primary lung tumours; cross‐kingdom MR1/MAIT and Dectin‐CARD9 signalling; and candidate host genetic determinants. The available human data are small, single‐centre and cross‐sectional, reporting association with brain‐metastasis status rather than prediction or causation; that bacteria accompany disseminating tumour cells into the brain remains a hypothesis awaiting paired sampling, spatial localization and experimental perturbation.We therefore reserve the term prevention for proposed trials, integrate microbial features with established molecular risk models, and specify the genetic‐perturbation program and research‐only decision pathway that would convert these claims into E1 evidence. Conclusions The microbiome–brain metastasis axis provides a hypothesis‐generating framework for investigating microbial contributions to cerebral dissemination. Multi‐centre validation, paired primary‐brain metastasis profiling and gnotobiotic models are required before microbiome‐directed strategies can be said to improve intracranial outcomes;until then this framework is hypothesis‐generating, not practice‐changing. Key points The proposed microbiome–brain metastasis axis links gut, lung and intratumoral microbial communities to intracranial dissemination in NSCLC. Current evidence remains insufficient to establish causality, with no proposed mechanism reaching the highest evidence level (E1). Five candidate mechanisms involve microbial metabolites, immune‐cell trafficking, intratumoral bacteria, MR1/MAIT and Dectin‐CARD9 signalling, and host genetic determinants. Multicentre validation, paired primary and brain metastasis profiling, spatial microbial localisation and experimental perturbation are needed to establish causality and assess clinical relevance. Microbiome‐directed prevention and therapeutic strategies remain investigational and should not yet inform routine clinical practice.
