Platinum-resistant ovarian cancer (PROC) responds poorly to platinum chemotherapy and evades immune surveillance by suppressing the cGAS-STING pathway, leading to poor outcomes. Herein, we developed an epigenetic metal-organic framework (MOF) nanoagonist (CMZ-Pt-SA@HA) that overcomes cisplatin (CisPt) resistance while restoring immune activation. The platform consists of Mn-ZIF-8 encapsulating CaO2 and co-loaded with CisPt and SAHA (a histone deacetylase inhibitor), then modified with hyaluronic acid to enable tumor targeting and controlled release. CMZ-Pt-SA@HA is multifunctional: SAHA downregulates resistance proteins epigenetically, CaO2 triggers calcium overload and oxygen release, and Mn2+/Zn2+ enhances oxidative stress and STING signaling, collectively strengthening chemo-metalloimmunotherapy. These mechanisms intensify CisPt-induced DNA damage and stimulate immune activation. CMZ-Pt-SA@HA applies a three-step "POP" strategy to overcome PROC's triple defenses: (I) Pre-targeting to enhance DNA-CisPt adducts; (II) On-targeting to block DNA repair; and (III) Post-targeting to induce apoptosis by relieving hypoxia, arresting the cell cycle, damaging mitochondria, and activating cGAS-STING. Whether used alone in subcutaneous tumors in preclinical ID8 and patient-derived xenograft mouse models, or combined with anti-PD-L1 therapy in ascites metastasis models, CMZ-Pt-SA@HA consistently showed strong therapeutic efficacy. Its Mn2+-based magnetic resonance imaging (MRI) capability further supports image-guided therapy and clinical translation.

Over 50% of global arable soils are acidic; acidic soil-induced aluminum (Al) phytotoxicity primarily inhibits root elongation, thereby reducing the plant's absorption of water and nutrients, which suppresses crop yield. Gibberellic acid (GA), a class of critical plant hormones, acts as a core regulator of plant development and growth mechanisms and contributes to the physiological adaptation of plants under stress conditions. In this study, we selected the rice variety Nipponbare (Nip) to investigate whether GA exerts an effect on alleviating Al toxicity and to explore the underlying mechanisms in rice. This study shows that Al stress quickly elevated the endogenous GA content in rice root tissues, consequently alleviating Al-induced suppression of root development. Exogenous GA application increased the expression of the Oryza sativa Cysteine-rich Peptide (Peptide with Cysteine-rich TDIF motif) 3 (OsCDT3) and Oryza sativa Ferric Reductase Defective Like 4 (OsFRDL4) genes, which reduce the toxicity of Al to plants and conversely decreased the expression of the Oryza sativa Natural Resistance-Associated Macrophage Protein 1 for Aluminum Transport (OsNRAT1) gene, which transports Al ions from the extracellular environment to the intracellular space. Furthermore, exogenous GA treatment modified the hemicellulose and pectin levels, therefore decreasing the absorption of Al. Further research shows that GA reduced the endogenous nitric oxide (NO) levels; nevertheless, the application of an exogenous nitric oxide donor sodium nitroprusside (SNP) offset the alleviatory role of GA. In conclusion, GA accelerated the cell wall Al exclusion mechanism, probably improving rice tolerance to Al toxicity via regulating the accumulation of NO.

Magnolia officinalis Rehder et Wilson (MRW) is a traditional herbal medicine with well-documented anti-inflammatory and antioxidative properties, yet its molecular basis in cancer therapy remains incompletely defined. This study aimed to elucidate the multi-target anticancer potential of MRW against pancreatic cancer through integrated in vitro and in silico analyses. LC-MS/MS profiling identified honokiol and magnolol as the major bioactive constituents, confirmed by retention time and UV spectra. MRW treatment suppressed cell viability and induced apoptosis in PANC-1 and MIA PaCa-2 cells by promoting reactive oxygen species (ROS) generation, mitochondrial membrane potential (∆Ψm) depolarization, and caspase activation, while sparing normal epithelial cells. Mechanistically, MRW inhibited DNA methyltransferase 1 (DNMT-1) and JAK2/STAT3 signaling while restoring undifferentiated embryonic cell transcription factor 1 (UTF-1) and miR-148a-3p expression, thereby reversing the epigenetic silencing and ROS overproduction characteristic of pancreatic cancer cells. Molecular docking further demonstrated strong binding affinities of honokiol, magnolol, and magnolin toward DNMT-1, UTF-1, STAT3, JAK2, IL-6, and Survivin, forming stable hydrogen-bond and π-π stacking interactions within catalytic pockets. These interactions suggest that MRW constituents' function as non-nucleoside DNMT-1 inhibitors and ROS-immune modulators that disrupt oncogenic feedback loops and re-activate apoptotic pathways. Collectively, these findings identify MRW as a multi-target phytomedicine integrating ROS-mediated oxidative stress, epigenetic remodeling, and immune-apoptotic signaling, supporting its translational potential as a low-toxicity adjunct strategy to conventional pancreatic cancer therapies.

Volatile organic compounds (VOCs) can prime plants for enhanced stress tolerance, yet how a brief volatile exposure is converted into sustained cold protection remains unclear. We established a sealed-headspace priming assay in Arabidopsis thaliana in which 7-day-old seedlings were exposed to short-chain reactive volatiles for 30 min, allowed to recover for 2 days, and then challenged by acute freezing (-20 °C). Screening green leaf volatiles revealed marked compound specificity: trans-2-hexenal and 4-hexen-3-one conferred strong protection, increasing post-freeze survival from ∼10-15% in controls to ∼55-65%, whereas several structurally related aldehydes were ineffective. Dose-response analyses uncovered a narrow effective window, with maximal survival at intermediate exposure levels and loss of protection at higher doses, consistent with a trade-off between priming and overexposure in a closed headspace. Although multiple volatiles rapidly induced HSFA2, early HSFA2 activation did not correlate with freezing tolerance across treatments. Transcriptome profiling immediately after a 30-min trans-2-hexenal exposure showed rapid induction of proteostasis and stress-related genes, together with enrichment of genes annotated to response to cold; canonical cold-responsive loci such as COR47 and COR413-PM1 were induced before freezing stress. Extending beyond Arabidopsis, a single trans-2-hexenal pretreatment also mitigated chilling injury in japonica rice, reducing necrosis and increasing green leaf area after cold exposure. Collectively, these results identify trans-2-hexenal as a rapid, dose-sensitive volatile signal that primes cold tolerance through coordinated activation of a stress-response transcriptome enriched in cold-response signatures, consistent with a mechanism that accesses cold-protective outputs without prior cold exposure.

Toosendanin (TSN) is the key bioactive component of Melia toosendan Sieb. et Zucc known for alleviating pain and expelling roundworms, but severe hepatotoxicity limited its further application. O-GlcNAcylation is a dynamic and reversible post-translational modification which has emerged as an important regulatory mechanism in cellular response to liver injury. In this study, we investigated the effect of aberrant O-GlcNAcylation and augmented O-GlcNAc signaling via Thiamet G (TMG) on TSN-induced ferroptosis in HepaRG cells. The O-GlcNAc transferase (OGT) expression and global O-GlcNAcylation level was significantly decreased accompanied by cell viability reduction and reactive oxygen species (ROS) production after the treatment with TSN. The western blotting and flow cytometry results showed that elevated O-GlcNAcylation by TMG treatment reversed the adverse changes induced by TSN in ferroptosis-related markers, including lipid ROS accumulation, glutathione depletion, and glutathione peroxidase 4 (GPX4) degradation. Additionally, immunoprecipitation demonstrated that TMG reversed TSN-induced nuclear factor erythroid 2-related factor 2 (Nrf2) O-GlcNAcylation inhibition and its ubiquitination enhancement in HepaRG cells. Furthermore, screening with the UbiBrowser database and mass spectrometry identified ubiquitin-specific protease 7 (USP7) as the potential deubiquitinating enzyme that mediates TMG-induced Nrf2 stabilization. In conclusion, TSN decreased global O-GlcNAcylation levels and increased the susceptibility of HepaRG cells to ferroptosis-associated hepatotoxicity by suppressing the Nrf2/GPX4 pathway.

Hypertension remains a significant global health issue. Low-density neutrophils (LDNs), a subset of neutrophils, contribute to vascular injury through immune activation. This study aimed to explore the effects of valsartan on LDNs in hypertension and to elucidate the molecular mechanisms underlying their role in therapeutic response. Newly diagnosed hypertensive patients received 80 mg/day valsartan for one month. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) collected before and after treatment. Mendelian randomization (MR) analysis was used to identify genes associated with valsartan response among the differentially expressed genes. Eleven cell subpopulations were identified, including four distinct LDN subtypes: CAMK1D, PI3, ISG15, and S100A12. Valsartan treatment reduced immune activation-related transcripts in LDNs, with decreased CAMK1D and increased PI3 expression. Lower MMP9 transcript levels in the PI3 subtype were linked to limited differentiation of LDNs into the CAMK1D subtype, with a preference for retention in the PI3 subtype, potentially contributing to valsartan's ehanced efficacy. Theses findings highlight CAMK1D and PI3 as LDN-related genes influencing valsartan response in hypertension, offering a foundation for future functional studies.

Drug resistance is a critical challenge in treating life-threatening fungal infections. Here, we uncover a mechanism of acquired azole resistance in Candida albicans through mutations in CAP1, encoding a conserved fungal transcription factor that mediates the oxidative stress response. We analyzed 300 clinical isolates and identified 25 distinct CAP1 missense or nonsense mutations, with many occurring within the DNA-binding domain. We identified two nearly identical CAP1 heterozygous nonsense mutations, one in an isolate obtained from a bloodstream infection and one in a population of cells undergoing adaptation to fluconazole in vitro. Both CAP1 nonsense mutations resulted in loss of the C-terminal nuclear export signal, leading to nuclear retention of Cap1 and subsequent activation of genes associated with the oxidative stress response and drug transport. The CAP1 C-terminal truncations conferred significant fitness advantages in the presence of fluconazole, both in vitro and in a murine model of candidiasis. Strikingly, we discovered a therapeutic vulnerability: azole concentrations above the minimal inhibitory concentration were fungicidal to mutants with the CAP1 C-terminal truncation. The fungicidal effect was attributed to both elevated azole-induced reactive oxygen species and a compromised oxidative stress response in Cap1-truncated cells. Our results provide novel characterization of de novo CAP1 point mutations emerging in both laboratory and clinical contexts, elucidate the mechanisms underlying Cap1-regulated stress responses, and reveal a potential therapeutic target for overcoming drug resistance in C. albicans infections.

In this study, we evaluated the impact of substituting conventional antifungal treatments with a commercial Tea Tree Oil (TTO) formulation in Rosa hybrida crop plants grown under controlled industrial conditions. Using a transcriptomic approach, we analyzed both leaves and petals to assess the molecular responses to TTO application. Our results revealed a pronounced transcriptomic shift in leaves, where 26 genes were significantly upregulated and one was downregulated, whereas petals displayed more subtle changes. The upregulated genes in leaves were enriched in pathways associated with lipid metabolism, cell wall modification, and plant defense, supporting the view that TTO acts as a bio-stimulant by activating stress-response transcriptional programs. In petals, the few upregulated genes included four transcriptional regulators, while the downregulated set encompassed lipase-like enzymes, cytochrome P450s, and a glucoside malonyltransferase. The comparatively diminished response in petals, which are functional specialized in pollination and have a more limited longevity compared to leaves, supports the view that systemic transcriptional adjustments are more evident in vegetative organs. These findings are consistent with previous reports of TTO's ability to modulate plant stress responses and reinforce its potential as a bio-based alternative to synthetic fungicides in sustainable floriculture.

Antimicrobial resistance (AMR) is a global health threat emerging through microbe adaptation, driven by genetic variation, genome plasticity or epigenetic processes. In this study, we investigated how the Mucor circinelloides species complex adapts to the antifungal natural product FK506, which binds to FKBP12 and inhibits calcineurin-dependent hyphal growth. In Mucor bainieri, most FK506-resistant isolates (90%) were found to be unstable and transient, readily reverting to being drug sensitive when passaged without drug, and with no associated DNA mutations. In half of the isolates (50%), FK506-resistance was conferred by RNAi-dependent epimutation in which small interfering RNAs (siRNAs) silenced the fkbA encoding FKBP12 post-transcriptionally. In contrast, most of the remaining FK506-resistant isolates (40%) were found to have undergone heterochromatin-mediated silencing via H3K9 dimethylation, transcriptionally repressing fkbA and neighboring genes. In these heterochromatic epimutants, only minimal enrichment of siRNA to the fkbA locus was observed, but in three of the four examples, siRNA was significantly enriched at a locus distant from fkbA. A similar mechanism operates in Mucor atramentarius, where FK506 resistance was mediated by ectopic heterochromatin silencing of fkbA and associated genes with siRNA spreading across the region. Heterochromatin-mediated fkbA epimutants exhibited stability during in vivo infection, suggesting epimutation could impact pathogenesis. These findings reveal that antifungal resistance arising through distinct, transient epimutation pathways involving RNAi or heterochromatin, highlighting adaptive AMR strategies employed by ubiquitous eukaryotic microbes.

Gene functions in Trypanosoma brucei parasites are investigated by several reverse genetic approaches. One of the widely used tools is the tetracycline-inducible system, which allows controlled overexpression of a gene of interest or knockdown of gene expression by RNA interference. For studying multiple genes, it is desirable to be able to control their expression independently or together, as required. A tetracycline- and vanillic acid-based double-inducible expression system was previously described for procyclic-form trypanosomes. Here, we describe the adaptation of this double inducible system to bloodstream-form trypanosomes. We show that this system can be used for stringent, independent, and simultaneous regulation of the expression of two genes.

Programmed cell death 1 ligand 1-targeted (PD-L1-targeted) immune checkpoint inhibitors are revolutionizing cancer therapy. However, strategies to induce endogenous PD-L1 degradation represent an emerging therapeutic paradigm. Here, we identified proanthocyanidins (PC) as a potent inducer of PD-L1 degradation through an endoplasmic reticulum-associated degradation (ERAD) mechanism. Mechanistically, PC exerted dual effects: First, it targeted and stabilized LKB1 to activate AMPK in tumor cells, subsequently inducing the phosphorylation of PD-L1 at Ser195 - a disruption that in turn impaired glycosylation of PD-L1 and promoted its retention in the ER. Second, PC directly bound to the E3 ubiquitin ligase SYVN1 to increase its protein stability, which strengthened PD-L1-SYVN1 binding, thereby accelerating K48-linked ubiquitination and proteasomal degradation of ER-retained PD-L1. This cascade culminated in the activation of CD8+ T cell-dominated antitumor immune responses, accompanied by suppression of myeloid-derived suppressor cells and regulatory T cells. In preclinical models of lung and colorectal cancer, PC exhibited synergistic antitumor efficacy when combined with anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) antibodies. Notably, PC also potently inhibited the progression of azoxymethane/dextran sodium sulfate-induced orthotopic colorectal cancer in mice. Collectively, our findings unveil an antitumor mechanism of PC, establishing this small-molecule compound as an ERAD pathway-exploiting immune checkpoint modulator with promising translational potential for cancer therapy.

Experimental evidence on the antioxidant role of arbutin, the main phenolic constituent in pear trees, remains limited. In this study, we investigated the effect of exogenous arbutin on the resistance of pear leaves to methyl viologen (MV)-induced oxidative stress. The results showed that arbutin application alleviated chlorophyll degradation and maintained higher photosynthetic efficiency under MV stress. Exogenous arbutin also attenuated the accumulation of malondialdehyde and H2O2 and promoted the activity of antioxidant enzymes. Additionally, exogenous arbutin had a mitigating effect on the MV-induced decline in phenolic accumulation and antioxidant capacity, as demonstrated by DPPH and FRAP assays. The expression of phenolic and arbutin biosynthesis-related genes (PAL, CHS, and UGT) significantly increased after MV exposure. Furthermore, arbutin-pretreated pear calli exhibited enhanced tolerance to cold, salt, and abscisic acid (ABA) stresses, characterized by elevated antioxidant enzyme activity and decreased oxidant levels. In tobacco leaves, transient overexpression of UGT enhanced arbutin accumulation and alleviated MV-induced oxidative damage. Collectively, these findings highlight the function of arbutin in controlling oxidative stress responses in pear leaves.

Understanding how plant roots manage co-occurring environmental stressors like nanoplastics (NPs) and arsenic (As) is critical, yet conventional methods often overlook their distinct strategic responses. Here, we developed and validated the Spatially-Dependent Interaction Framework (SDIF), a unified statistical model designed to deconstruct complex multi-stressor interactions across biological compartments. Applied to a high-resolution transcriptomic dataset from rice (Oryza sativa) co-exposed to environmentally relevant levels of NPs (1 mg L-1) and As (1 mg L-1 As(III)), our analysis revealed that roots employ a predominantly additive defense strategy, with virtually no significant nonadditive molecular interactions (1 gene). This contrasts sharply with the systemic response in leaves, where complex antagonistic interactions were prevalent (40 genes), indicating a distinct role in systemic damage control. Crucially, the SDIF's direct test for three-way interactions (Stressor A × Stressor B × Tissue) pinpointed the iron homeostasis protein Ferritin 1 (OsFer1) as a key regulator of this divergent strategy. OsFer1 exhibited synergistic amplification in roots (interaction log2-fold change [LFC] = +1.27), consistent with a fortified frontline defense, which is reversed to an antagonistic suppression in leaves (LFC = -0.85). This critical finding, obscured by traditional analyses, highlights SDIF's utility in uncovering nuanced, organ-specific toxicodynamic strategies. It underscores the importance of a root-centric perspective for the risk assessment of contaminant mixtures in food crops.

The accumulation of excess manganese (Mn) is toxic to plants and limits agricultural productivity. Although selenium (Se) is known to be a beneficial element that can alleviate heavy metal stress, its role in mitigating Mn-related stress remains insufficiently explored. This research explores the effects of Se (applied as sodium selenite at 0.5 μM) on 0.5 mM Mn toxicity in Malus robusta seedlings, focusing on Mn accumulation, physiological performance, polyamine metabolism, proline biosynthesis, and the enzymatic activity and expression levels of critical genes. Exogenous Se significantly reduced Mn accumulation and alleviated Mn toxicity, as evidenced by enhanced root growth, increased photosynthetic pigments, improved fluorescence parameters (Fv/fm and ΦPSII), and maintained antioxidant balance via a reduced production of reactive oxygen species (ROS) and an activation of the antioxidant system. Moreover, total putrescine (Put) and spermine (Spm) contents declined after Se application, whereas spermidine (Spd) levels showed no noticeable change. This led to an increased (Spd + Spm)/Put ratio, highlighting the pivotal role of Put reduction in Mn stress response. A decrease in Put corresponded with significant downregulation of ornithine decarboxylase (ODC; EC 4.1.1.17) and arginine decarboxylase (ADC; EC 4.1.1.19) activities and gene expressions. Furthermore, soluble conjugated and insoluble bound polyamines followed a similar trend, except for a notable increase in bound Spd. In addition, Se treatment decreased proline (Pro) content mainly through the suppression of ornithine aminotransferase (OAT; EC 2.6.1.13). It is observed that Se enhances the ability of M. robusta to withstand Mn stress by regulating polyamine and proline metabolism, thereby highlighting a possible mechanism for reducing Mn toxicity in plants.

The ubiquitin-proteasomal protein degradation system is a key regulatory process mediating the dehydration stress response in plants, and RGLG proteins, a subfamily of the RING E3 ligases, are well known to modulate this response. In this study, we isolated four SlRGLG proteins (Solanum lycopersicum RING domain ligase) from tomato plants and characterized their functions at the molecular and biological levels. We found that these four SlRGLGs have the conserved VWA and RING domains and high amino acid sequence identities with RGLGs from Arabidopsis thaliana and pepper plants. The transcript levels of SlRGLGs were found to be responsive to several environmental stimuli, including dehydration, mannitol, and abscisic acid, which are believed to be associated with the presence of different stress-associated cis-regulatory elements in the respective promoter regions. Subcellular localization studies of SlRGLGs-GFP fusion proteins revealed distinct subcellular distribution patterns, and all four MBP-SlRGLGs recombinant proteins exhibited robust E3 ligase activities in vitro. To elucidate their biological roles in the dehydration stress response, we generated SlRGLGs-silenced tomato plants and SlRGLGs-overexpressing (OE) Arabidopsis plants. Notably, all SlRGLGs-silenced tomato plants were found to have dehydration-sensitive phenotypes with increased transpirational water loss and lipid peroxidation of cell membranes and decreased expression of dehydration stress-responsive genes. However, all SlRGLGs-OE Arabidopsis plants showed the dehydration-tolerant phenotypes, compared to control plants. Collectively, these findings indicate a positive role for all four SlRGLGs in the dehydration stress response of tomato.

Polyphenols, abundant in tea, fruits, vegetables, and other plant-derived foods, have emerged as key bioactive ingredients in the field of nutritional epigenetics. These polyphenols can modulate epigenetic modifications through endogenous metabolic pathways that are highly sensitive to food signals. Among these, the methionine cycle plays a central role in maintaining the homeostasis of DNA, histone, and RNA methylation by controlling the cellular supply of S-adenosylmethionine (SAM), the universal methyl donor. Dietary polyphenols influence this cycle through multiple mechanisms, including the regulation of methionine adenosyltransferase activity, modulation of SAM biosynthesis, and promotion of S-adenosylhomocysteine clearance. These actions help restore methylation balance and contribute to the dietary prevention of metabolic, inflammatory, and age-related diseases. Furthermore, polyphenols are biotransformed in the gut microbiota to produce metabolites that further influence methionine metabolism and its associated epigenetic modifications. This review provides an overview of dietary polyphenols as functional food supplements that play a role in methionine metabolic homeostasis and epigenetic modification. This review provides new perspectives for the development of precision nutrition strategies, functional foods, and chronic disease prevention approaches.

Per- and poly fluoroalkyl substances (PFAS) pose significant global health risks. Although the use of classical PFAS such as perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) is regulated, the toxicological effects of alternative PFASs remain unknown. Cleft palate is a congenital condition influenced by both environmental and genetic factors. Although PFOS has been linked to cleft palate, the effects of other PFAS compounds remain unexplored. The aim of this study was to clarify the involvement of classical and alternative PFAS (PFHxA and PFHxS) in human embryonic palatal mesenchymal cell (HEPM) proliferation. Following PFAS treatment for 48 h, cell viability, apoptosis, and expression of cell cycle-related proteins were tested. In addition, miRNA levels and predicted target genes were measured, and a rescue experiment against PFHxS was conducted using an miR-374a-5p inhibitor. Among the four PFASs, PFHxS decreased the number of cells showing cyclin- and cyclin-dependent kinase reduction. In addition, PFHxS treatment upregulated miR-374a-5p and downregulated its downstream genes. Furthermore, miR- 374a-5p inhibitor alleviated the PFHxS-induced reduction in cell proliferation. These findings therefore indicate that miR-374a-5p plays a key role in the development of PFHxS-induced cleft palate and that alternative PFAS may have a highly toxic effect on HEPM cells.

Ginkgetin, a biflavonoid from Ginkgo biloba, is known for its anti-inflammatory and antioxidant properties, but its effectiveness and mechanism in treating osteoarthritis (OA) are not well understood.

Diabetic nephropathy (DN), a leading cause of end-stage renal disease, lacks curative therapies. Podocyte injury plays a central role in DN progression, yet strategies to effectively preserve podocyte integrity remain limited. Shenxiao decoction (SXD) is a classic Traditional Chinese Medicine (TCM) prescription, derived from Buzhong Yiqi Decoction and Xuefu Zhuyu Decoction, widely used clinically for DN. However, the molecular mechanisms of podocyte protection are poorly understood.

Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.