Although inhibitors of oncogenic KRAS have shown clinical efficacy1, resistance to KRAS inhibition is common2, and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3Kα signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3Kγ-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3Kγ signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.

Recent evidence shows that fatty acid synthase (FASN), a key regulator of de novo lipogenesis (DNL), is a promising therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD). FASN inhibitors are under advanced clinical trials. In this study, we evaluated the therapeutic efficacy of a novel FASN inhibitor 84-B10 for the treatment of MASLD. RNA-seq analysis showed that FASN was significantly upregulated in PA/OA-treated mouse primary hepatocytes. In silico molecular docking screening combined with biochemical assay, 84-B10 exhibited the strongest FASN-inhibiting effect. We demonstrated that 84-B10 directly bound to the MAT domain of FASN, inhibiting its enzymatic activity and promoting its ubiquitination and proteasomal degradation. In mouse primary hepatocytes, 84-B10 induced Lys48-linked ubiquitination of FASN by recruiting the E3 ligase tripartite motif-containing 28 (TRIM28), leading to FASN protein degradation. In PA/OA-treated mouse primary hepatocytes, 84-B10 (5, 10 μM) dose-dependently ameliorated lipid accumulation and mitochondrial dysfunction. In HFD-fed mice, administration of 84-B10 (5 mg/kg, i.g. every other day for 6 weeks) significantly alleviated metabolic alterations and hepatic lipid accumulation. Our results establish 84-B10 as a novel FASN inhibitor that activating the FASN-TRIM28 axis by binding to the MAT domain, facilitating the proteasomal degradation of FASN. With favorable safety, tolerability, and pharmacokinetic properties, 84-B10 holds promise as a therapeutic candidate for the prevention and treatment of MASLD.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the following anomalies/potential areas of concern appeared to be associated with the western blot data featured in Figs. 2, 4 and 6 (including the description of additional features that came to light based upon an independent analysis of the data in this paper that was undertaken by the Editorial Office):  i) There were overlapping data bands comparing the cyclin D1 and β‑actin bands in Fig. 2C and D with those in Fig. 4B, where the figure legends indicated that the experimental conditions for these figures were different; and ii) in Fig. 6A, two pairings of cyclin D1 blots appeared to be duplicated/doubled up (giving rise to four sets of blots), and moreover, the associated β‑actin blots also appeared to exhibit different overlaps of individual bands/pairs of bands. Given the identification of so many instances of data duplication comparing both within and between the abovementioned figures in this paper, the Editor has decided that this paper should be retracted from the Journal on account of a lack of confidence in the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 12: 4396‑4402, 2015; DOI: 10.3892/mmr.2015.3912].

3114 Background: Molecular profiling of cholangiocarcinoma (CCA) is highly recommended to guide access to targeted therapies such as FGFR2 inhibitors. 3HP-2827 is a highly selective and potent FGFR2 inhibitor targeting FGFR2 alterations. Here we report the findings of 3HP-2827 in advanced solid tumors harboring FGFR2 alterations. Methods: This is a phase I/II study to evaluate the safety, tolerability, PK, and preliminary efficacy of 3HP-2827 in pts with advanced solid tumors harboring FGFR2 alterations. Pts failed to standard therapy with/without prior pan-FGFR inhibitor (FGFRi) are eligible for enrollment. Bayesian Optimal Interval (BOIN) and back filling design were employed in the dose-escalation stage of phase I, followed with the expansion stage. Treatment-related adverse events (TRAEs), PK, and anti-tumor activity (RECIST v1.1) were assessed. Results: As of Jan 8, 2026, a total of 52 pts (46 with CCA, 6 with others) were enrolled from 12 centers, received 3HP-2827 at doses of 60-180 mg once daily (QD), including 42 with FGFR2 fusion/rearrangement (f/r), 6 with FGFR2 mutation. 19 pts (36.5%) had prior FGFRi. No dose-limiting toxicities (DLTs) were observed at the dose levels of 60 mg, 120 mg, 180 mg QD. 3HP-2827 had favorable PK with doses≥120 mg QD providing FGFR2 occupancy＞90%. The most common TRAEs were FGFR2 on-target toxicities including dry mouth (69.2%, G3 1.9%), nail toxicity (67.3%, G3 3.8%), stomatitis (50%, G3 3.8%), dry eyes (26.9%, G3 1.9%), PPE (19.2%, G3 3.8%). 12 pts (23.1%) experienced at least one G3/G4 TRAE and no G5 TRAEs occurred. 7 pts (13.5%) experienced at least one serious adverse event, 4 (7.7%) of them were considered related to 3HP-2827. No discontinued treatment or death due to TRAEs. Anti-tumor activities were observed from 60 mg QD. Among 15 CCA pts (FGFR2 f/r, FGFRi-naive) who had at least one post-treatment tumor assessment, objective response rate (ORR) was 80% (95% CI: 51.9, 95.7), and disease control rate (DCR) was 100% (95% CI: 78.2, 100). The ORR and DCR in 15 CCA pts (FGFR2 f/r, FGFRi-refractory) was 26.7% (95% CI: 7.8, 55.1) and 86.7% (95% CI: 59.5, 98.3). The ORR and DCR in 4 advanced solid tumor pts (FGFR2 mutation, FGFRi-naive) was 75% (95% CI: 19.4, 99.4) and 100% (95% CI: 39.8, 100). Conclusions: 3HP-2827 was found to be safe and tolerable, with encouraging anti-tumor activity observed in pts with FGFR2 alterations. Further clinical efficacy will be explored in the expansion stage and phase II stage. Clinical trial information: NCT06378593 .

5544 Background: Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16 and HPV18, drives the development of high-grade squamous intraepithelial lesions (HSIL), an obligate precancerous condition. The standard care of cervical HSIL requires either surgical excision (LEEP or cold-knife conization), or in some circumstance, watchful waiting. AFN0328 is a novel mRNA-based immunotherapy encoding HPV16/18-related antigens, designed to elicit antigen-specific immune responses and interrupt viral antigen-driven disease progression. Methods: Safety, tolerability and preliminary efficacy of AFN0328 were assessed in patients with HPV16- and/or HPV18-associated HSIL (CIN2/3) in an ongoing, multicenter, open-label Phase 1 trial. The study comprised two sequential parts: Part 1 employed a classic 3+3 dose-escalation design to assess safety and determine the maximum tolerated dose (MTD); Part 2 is a dose-expansion cohort at selected doses (150 μg and 300 μg) to further characterize safety, tolerability, and preliminary efficacy. AFN0328 was administered intramuscularly at 0, 4, and 12 weeks. The primary endpoints included safety and tolerability (dose-limiting toxicities within 28 days post-first dose, adverse events graded per CTCAE v5.0). For Part 2, the efficacy endpoints included viral clearance rate at Week 24 and Week 36, and histopathological regression at Week 36. Secondary endpoints included pharmacokinetic parameters, HPV16/18-specific IgG antibody titers, and pharmacodynamic markers (cellular immune responses and serum cytokines). Results: As of December 29, 2025, 23 patients had received at least one dose of AFN0328. No DLTs, serious adverse events, or grade ≥3 treatment-related adverse events (TRAE) were observed. PK analyses of first and last doses showed that circulating mRNA encoding HPV-related antigens peaked within 48 hours and declined gradually, with detectable levels persisting for up to at least 4 weeks across dose levels. All evaluable patients developed specific IgG responses and viral clearance was observed in evaluable patients during follow-up. Conclusions: AFN0328 demonstrated favorable safety and tolerability with robust immune responses in HPV16/18-associated HSIL, supporting further clinical development as an immunotherapy for HPV-driven precancerous disease. Clinical trial information: CTR20244013. Summary of safety and immunogenicity outcomes. Outcome Result Patients treated 23 Dose-limiting toxicities 0 Grade ≥3 treatment-related AEs 0 Most common TRAEs Injection-site reactions, fever Specific IgG response rate 100%* Observed viral clearance Yes* *Observed in evaluable patients during interim follow-up.

Inflammation and stroma remodeling regulate pancreatic ductal adenocarcinoma (PDAC), but how or if these cues are integrated at the molecular level remains unclear. Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor DDR1, and subsequent tumorigenesis. We show that defective Col-I remodeling deprives PDAC cells of the high affinity DDR1 ligand, ¾Col-I, resulting in reduced ATP and activation of AMPK. AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent degradation. Importantly, this degradation pathway can be disabled by inflammatory signaling. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, which establishes an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-κB-NRF2 signaling even in restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly called NASH, is a progressive form of fatty liver disease closely linked to metabolic dysregulation. It has become a leading cause of liver failure and liver transplantation worldwide. Despite its growing clinical significance, there is currently no centralized, publicly accessible, cross-cohort and cross-species transcriptomic database specifically dedicated to MASH. To address this gap, we developed MASH-GA (MASH-Genomic Atlas; https://mashga.com), the first and only database in the fatty liver research field that systematically integrates transcriptomic data across human cohorts and mouse models. MASH-GA contains 45 human transcriptomic datasets (2740 samples) from 17 countries and 126 mouse datasets (1950 samples) covering major MASH models. The platform provides a range of unique features, including integrated weighted gene coexpression network analysis (WGCNA), cross-model classification and comparison of mouse datasets, multigene correlation analysis and pairwise coexpression exploration, and interactive visualizations (e.g. boxplots and correlation plots). Human and mouse data are presented in separate, intuitively navigable modules. As the only standardized, multicohort, cross-species MASH transcriptomic database currently available, MASH-GA enables reproducible data exploration, informed model selection, and the identification of regulatory modules. It is therefore a valuable resource for researchers in hepatology, metabolic disease, and systems biology. Database URL:  https://mashga.com.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are leading causes of chronic liver disease worldwide. Increasing evidence indicates that hepatic macrophages play central roles in disease development and resolution. However, their functional heterogeneity has only recently been recognized. Hepatic macrophages consist of embryonically derived Kupffer cells and monocyte-derived macrophages, which undergo dynamic phenotypic and metabolic remodeling in response to lipid overload, inflammation, and tissue injury. Recent single-cell, spatial, and multi-omics studies have identified lipid-associated macrophages (LAMs) as a distinct macrophage program enriched in MASLD/MASH. LAMs are characterized by enhanced lipid-handling capacity, lysosomal activation, and lipid-sensing transcriptional programs involving triggering receptor expressed on myeloid cells 2 (TREM2), peroxisome proliferator-activated receptor γ, liver X receptor α, and microphthalmia-associated transcription factor. Spatially, TREM2+ LAMs localize to steatotic and fibrotic niches, where local lipid and inflammatory cues shape their chromatin accessibility and functional states. This heterogeneity enables divergent roles in inflammation, metabolic regulation, fibrogenesis, and disease resolution, offering opportunities for stage-specific therapeutic intervention. This review summarizes the understanding of hepatic macrophage heterogeneity in MASLD/MASH, with a focus on lipid-associated programs, molecular mechanisms, spatial organization, and functional plasticity across disease stages. We also discuss emerging therapeutic strategies targeting specific macrophage subsets and pathways, and highlight the need for spatiotemporally precise modulation of macrophage functions in future therapeutic development.

Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2high PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1high human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKKα-deficient KrasG12D/IkkαΔPEC mice in which NRF2 is strongly activated, immunocompromised Nu/Nu mice orthotopically transplanted with human PDAC cells and C57BL/6n and NOD/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8+ T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2high PDAC.

The cancer-immunity cycle (CIC) provides a conceptual framework for eliciting effective anti-tumor immune responses by targeting key events in systemic immunity. However, the successful completion of the CIC often requires the coordinated action of multiple therapeutic modalities, necessitating their integration into a unified system to overcome the limitations of conventional combination therapies. Here, we present a multimodal and programmable platform that integrates diverse therapeutic biomolecules into single agents, enabling the construction of versatile nanomedicines and bispecific antibodies through dual-targeted nano-adaptor (TNA) nanotechnology to potentiate the CIC. Specifically, TNA nanomedicines target five critical steps within the CIC, including antigen release, dendritic cell (DC) maturation, T-cell activation, mitigation of T-cell exhaustion, and tumor cell killing. Meanwhile, TNA bispecific antibodies enhance DC-T cell interactions to strengthen adaptive immunity and reinforce NK-tumor cell interactions to promote cytotoxicity. We demonstrate that TNAs elicit robust anti-tumor immunity, eradicating established tumors and suppressing metastatic dissemination. Owing to their modular and programmable architecture, TNAs hold broad potential for applications in immunotherapy and beyond.

primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.

The conventional biomarker discovery approach in metabolomics treats metabolites as isolated features, failing to capture their interdependencies. We applied a network-based method using Tabular Prior-Data Fitted Networks (TabPFN) integrated with SHapley Additive exPlanations (SHAP) to derive stage-specific metabolic networks capturing statistical metabolite co-contribution patterns and identify key metabolites. We analyzed 1312 participants across five stages (control, hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC)), quantitatively profiling 160 metabolites, and externally validated the results in 721 samples. We compared three approaches: (1) TabPFN-SHAP, (2) conventional statistics with machine learning, and (3) TabPFN-SHAP integrated with literature-validated biomarkers. TabPFN-SHAP–based approaches outperformed the conventional pipeline, revealing distinct stage-specific metabolic signatures with overlapping metabolites between consecutive networks, marking consistently prioritized features. A five-metabolite HCC-screening panel (sebacic acid, alpha-linolenic acid, phenylalanyl-tryptophan, arachidonic acid, and glycocholic acid) was identified. At the screening-oriented cutoff, the panel achieved an AUROC of 0.979 (95% CI: 0.966–0.991) for Control vs HCC and 0.955 (95% CI: 0.936–0.977) for Fibrosis/Cirrhosis vs HCC, with sensitivity of 0.937, specificity ≥0.855, accuracy ≥0.897, and negative predictive value ≥ 0.981 across both clinical scenarios, outperforming all comparative approaches. TabPFN-SHAP provides an interpretable computational framework for metabolite-panel discovery, with demonstrated utility for HCC screening.

Abstract This study investigated the roles of the NLRP3 inflammasome in postoperative ileus (POI) pathogenesis. Male BALB/c mice were randomly divided into sham, POI, and MCC950 (NLRP3 inhibitor) groups. Intestinal motility was assessed 24 h postoperatively. RNA‐seq was performed. Histopathological changes were evaluated through H&E and immunofluorescence; CAT and POD activities in the intrinsic muscle layer were detected; Western blot was used to detect NLRP3, GSDMD‐N, cleaved caspase‐1, and p‐NF‐κB p65 expressions; ELISA was used to detect blood IL‐1β, TNF‐α, IL‐6, and IL‐10 levels. RNA‐seq analysis showed 152 differential genes in the POI group, including NLRP3. In intestinal tissue of the POI mice, NLRP3 expression and expressions of GSDMD‐N, cleaved caspase‐1, and p‐NF‐κB p65 increased. IL‐1β, TNF‐α, IL‐6, and IL‐10 levels increased, while CAT, POD, and SOD activities decreased. The postoperative small intestine advancement rate of POI mice was reduced. After MCC950 intervention, the pathological damage to intestinal tissue and the intestinal function were restored, and the small intestine advancement rate was improved. Meanwhile, MCC950 effectively inhibited the activation of the NLRP3 inflammasome. NLRP3 inflammasome activation drives the pathogenesis of POI and MCC950 can effectively alleviate intestinal injury.

Background The ECM-receptor interaction signaling pathway is essential for the progression of various tumors. Histamine N-methyltransferase (HNMT), a histamine metabolic enzyme, is significantly upregulated in hepatocellular carcinoma (HCC). However, the impact of HNMT on tumor progression through regulation of the ECM-receptor interaction signaling pathway within the tumor microenvironment remains unclear. This study explores HNMT as a potential candidate target gene for HCC treatment and investigates its mechanism of action. Methods The HNMT target gene was overexpressed in the liver cancer cell line MHCC97L, while the HNMT gene was knocked down in HepG2 cells. Differentially expressed genes were identified using a combination of transcriptomic and proteomic analyses. Validation of differentially expressed proteins was performed through q-PCR and Western blotting. Results HNMT consumption of the intracellular methyl pool leads to the suppression of histone H3K9 trimethylation (H3K9me3), resulting in elevated expression of VTN and activation of the ECM-receptor interaction signaling pathway. This biological process enhances the proliferation, vascular adhesion, and invasion capabilities of HCC cells. However, whether the changes in VTN gene expression are directly governed by H3K9me3 modification remains to be further verified experimentally. Conclusion HNMT facilitates HCC progression via modulating histone methylation. The HNMT-VTN axis offers new insights for HCC targeted therapy.