Lipid metabolism disorders and increased angiogenesis play key roles in the tumorigenesis of hepatocellular carcinoma (HCC). Intracellular metal ion disorders such as cuproptosis and ferroptosis have been progressively identified. However, whether copper ions have other effects outside the already recognized mechanisms of cell death is just as worthy of investigation. In particular, the effects on lipid metabolism and angiogenesis have important roles in the development of HCC. Our study revealed that disulfiram (DSF), a copper ion carrier, not only had a significant antitumor effect in vitro and in vivo, but also significantly inhibited angiogenesis and reversed abnormal lipid metabolism. Through transcriptome analysis, m1A methylation analysis, and functional validation, we identified c-FOS as a key target in DSF-induced methylation changes. In summary, DSF can reduce the modifications of c-FOS caused by the m1A methyltransferase TRMT10C, then regulate downstream genes MCAM and PCSK9, ultimately affecting angiogenesis and lipid metabolism. Moreover, high levels of expression of TRMT10C and PCSK9 in human HCC tumor tissues were associated with poor prognosis, while c-FOS showed the opposite pattern, confirming that the TRMT10C-c-FOS-PCSK9 axis is an important mechanism in HCC. In conclusion, copper ion carrier-DSF promotes the expression of c-FOS by inhibiting the m1A methyltransferase TRMT10C, thereby reversing the dysregulation of lipid metabolism and inhibiting angiogenesis in HCC.

Cancer-associated fibroblasts (CAFs) are necessary constituents of the tumor microenvironment, significantly promoting cancer cell proliferation, invasion, and therapeutic resistance through the secretion of various factors. This study elucidates a novel metabolic-epigenetic mechanism by which glutathione peroxidase 8-positive (GPX8⁺) CAFs confer lenvatinib resistance in hepatocellular carcinoma (HCC). We demonstrate that GPX8 overexpression in CAFs activates the PI3K/AKT/mTOR signaling pathway by suppressing endoplasmic reticulum stress, driving glycolytic reprogramming and lactate production. HCC cells import this CAF-derived lactate via monocarboxylate transporter 1 (MCT1), elevating histone H3 lysine 18 lactylation (H3K18la) levels. Increased H3K18la enrichment at the promoter of bromodomain and PHD finger-containing protein 1 (BRPF1) transcriptionally upregulates BRPF1 expression. Furthermore, we found that BRPF1 mediates lenvatinib resistance in HCC by promoting H3K14ac and inducing activation of the EGFR pathway. Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo. These findings establish the GPX8⁺ CAF/lactate/MCT1/H3K18la/BRPF1/EGFR axis as a pivotal driver of lenvatinib resistance and identify MCT1 and BRPF1 as actionable therapeutic targets for overcoming resistance in HCC.

Hepatoblastoma (HB) is the most common malignant liver tumor in children, with limited treatment options. The N4-acetylcytidine (ac4C) modification, an important mRNA post-transcriptional modification catalyzed by N-acetyltransferase 10 (NAT10), plays a crucial role in the initiation and progression of tumors. However, its impact on the development and prognosis of HB is largely unknown. This study demonstrates that NAT10 is notably upregulated in HB. NAT10 inhibition suppressed HB proliferation and metastasis in vitro and in vivo. Mechanistically, Yes-associated protein 1 (YAP1) induced NAT10 transcription by binding to its promoter, which stimulates the ac4C modification within the 3' untranslated region (3' UTR) of glucose-6-phosphate dehydrogenase (G6PD) and enhancing its mRNA stability. YAP1/NAT10/G6PD axis resulted in enhanced pentose phosphate pathway (PPP) to promote proliferation and metastasis of HB. Moreover, said NAT10-mediated oncogenic effect could be significantly attenuated by a NAT10 inhibitor (Remodelin) both in vitro experiments and in vivo HB mouse models. Overall, our findings revealed the oncogenic role of NAT10 in regulating HB growth and metastasis, which can be a potential therapeutic target for human HB.

Hepatocellular carcinoma tumor-repopulating cells (HCC-TRCs) drive disease progression, yet their purine metabolism mechanisms remain poorly understood. This study revealed that the stemness index, strongly linked to poor HCC prognosis, exhibited a robust positive correlation with purine metabolism through single-sample gene set enrichment analysis. Integrated drug screening across CTRP, GDSC, and PRISM databases identified alisertib, an aurora kinase A (AURKA) inhibitor, as a potent agent targeting stemness. Using fibrin gel-based 3D-cultured HCC-TRCs, mechanistic studies demonstrated that alisertib suppresses xanthine and hypoxanthine production by inhibiting the AURKA-AKT signaling axis. This disruption markedly impaired tumor spheroid formation, migration, and invasion in vitro, while significantly suppressed tumor growth in vivo, which could be rescued by the AKT agonist SC79. Our findings revealed a novel therapeutic strategy targeting purine metabolism through AURKA-AKT axis inhibition, effectively eliminating HCC-TRCs.

Osteosarcoma is the most common primary bone malignancy, with a very poor prognosis. Aberrant glycosylation is close involvement in osteosarcoma. Accordingly, this study aimed at investigating the role of glycosylation genes in the prognosis and therapy options of osteosarcoma. The microenvironment of osteosarcoma was assessed using estimate algorithm. A total of 20 immune-related glycosylation genes (IRGGs) was identified using Pearson correlation analysis. Accordingly, osteosarcoma patients were divided into C1 and C2 type using consensus clustering. Multiple algorithms (Xcell, MCP-counter, ssGSEA, epic, quantiseq), cancer immune cycle analysis, and GSVA were applied to estimate the immune, molecule and metabolism characteristics of osteosarcoma, indicating that C1 type was featured with high immune infiltration, high glycosylation, enriched MEK signaling, and good prognosis, while C2 type was characterized by more metastasis, enriched immunotherapy-positive gene signatures, high tumor mutation burden, and poor prognosis. Results from TIDE algorithm and immunotherapy datasets suggested the C2 type's preference of immune checkpoint inhibitors (ICIs), while data of GDSC, CMap analysis and cell experiments indicated that C1 type was sensitivity to MEK inhibitor PD0325901. In addition, univariate Cox and Lasso analysis was combined to establish an IRGGs' risk score containing 6 genes (B3GNT8, FUT7, GAL3ST4, GALNT14, HS3ST2, and MFNG). The data of DCA and ROC indicated its well prediction of prognosis in osteosarcoma. Finally, cellular location analysis showed that the 6 genes not only distributed in tumor cells but also in immune cells. In summary, the classification and risk score based on IRGGs effectively predicted the prognosis and therapy options of osteosarcoma. Further studies on IRGGs may contribute to the understanding of cancer immunity in osteosarcoma.

INTRODUCTION:The new working submucosal tunnel space allows entry to deeper layers of the luminal wall or even entirely outside the gastrointestinal tract for the treatment of submucosal tumors. Based on this concept, we developed submucosal tunneling endoscopic resection (STER). Here, we compared the clinical outcomes between exposed endoscopic full-thickness resection (EFTR) and STER (nonexposed EFTR) and analyzed the efficacy and safety of Natural Orifice Transluminal Endoscopic Surgery (NOTES) based on STER for extra-gastrointestinal stromal tumors (EGISTs). METHODS:Sixty consecutive patients with tumors in the lesser curvature of the stomach corpus were enrolled from July 2019 to December 2023. Data on clinicopathologic features, treatment results, and follow-up outcomes were collected and analyzed retrospectively. RESULTS:Among the 60 patients, 31 patients underwent EFTR and 29 patients underwent STER. The EFTR group had a shorter procedure time ( P = 0.016) but a longer postoperative hospital stay ( P = 0.004) than the STER group. Tumor size > 2 cm and endoloop-clips suture were significantly associated with long-time procedure. NOTES based on STER was successful for EGISTs. Follow-up data from 6 to 60 months was collected with no loss. All patients were free from local recurrence and distant metastasis during the study period. CONCLUSIONS:Although the procedure time of STER is longer than that of EFTR, the postoperative hospital stay is shorter. Tumor size > 2 cm and use of endoloop-clips suture are significantly associated with long-time procedure. In addition, STER-based NOTES is a promising and safe methodology for the resection of EGISTs.

Prevalence of gastroesophageal reflux disease (GERD) has shown an upward trend over the years. Even though patients with GERD have a poor quality of life, the current treatment options are highly limited. In recent years, however, the development of anti-reflux mucosal intervention (ARMI), a novel strategy for treating GERD, has provided hope to such patients. ARMI comprises three main steps: Anti-reflux mucosectomy, anti-reflux mucosal ablation, and peroral endoscopic cardial constriction. ARMI involves the constriction of the pericardial mucosa through endoscopic surgery so as to reduce the damage caused by the reflux of gastric contents. This study compares different ARMI techniques, their therapeutic efficacy in treating GERD, indications and contraindications, endoscopic operational procedures, perioperative management, and adverse events, in an attempt to provide clinical guidance.

Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8’s role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients’ data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3β from the Wnt/β-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven β-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3β, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC.

Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy that currently lacks effective clinical treatments. Eliminating stem cell-like cancer cells is an extremely promising but challenging strategy for treating ICC. A recently developed synthetic retinoid, sulfarotene, abrogates proliferation, and induces apoptosis of tumor-repopulating cells (TRCs) that exhibit stem cell-like properties, yet its effect and underlying mechanisms remain elusive in ICC. It is found that although 5-fluorouracil, cisplatin, pemigatinib, and gemcitabine all inhibit ICC-TRCs, sulfarotene demonstrates superior efficacy. Sulfarotene induces retinoic acid receptor alpha (RARɑ) translocation from the cytoplasm to the nucleus, suppressing P-selectin expression at the transcriptional level. Moreover, it directly interacts with fucosyltransferase 8 (FUT8), inhibiting the core fucosylation of P-selectin glycoprotein ligand 1 (PSGL1). These actions collectively inhibit ICC-TRCs via destroying PSGL1-regulated cytoskeleton. The findings provide a strategy of inhibiting P-selectin/PSGL1 interaction and altering PSGL1 glycosylation pattern to compromise the cytoskeletal integrity and eliminate ICC-TRCs.

As an important first-line drug for advanced hepatocellular carcinoma（HCC）, lenvatinib shows non-inferior therapeutic effects to sorafenib as well as better performance in certain aspects. However, lenvatinib resistance emerged eventually as most other anticancer drugs. Epidermal growth factor receptor（EGFR） bypass activation, the overexpression of fibroblast growth factor receptor 1（FGFR1） and the appearance of cancer stem cells in HCC are the causes of lenvatinib resistance. Lenvatinib combined with immune checkpoint inhibitors（ICIs） has been proven to have good efficacy in clinical trials. This review summarizes the new research findings on the mechanism of lenvatinib resistance and new strategies for improving the efficacy of lenvatinib in recent years, which could be helpful for treatment of HCC patients with lenvatinib.

The senescence-associated secretory phenotype (SASP) is closely associated with the tumorigenesis and progression of intrahepatic cholangiocarcinoma (ICC). However, it remains unclear its relation to stemness of ICC. In the study, the stemness indices of ICC were calculated using one-class linear regression (OCLR) and single-sample gene set enrichment analysis (ssGSEA) algorithms. A total of 14 senescence-related stemness genes (SRSGs) were identified using Pearson correlation analysis in ICC. Subsequently, a SRSGs-related classification was established using a consensus clustering for ICC. Different types of ICC exhibit distinct prognosis, immunity, metabolisms, and oncogenic signatures. Additionally, we constructed a risk score model for ICC using principal component analysis (PCA). The risk score was positively correlated with stemness, immune infiltration, metabolisms and oncogenic signatures, but negatively with prognosis in ICC. Patients with a high risk score may respond well to immunotherapy. Furthermore, we employed 3D fibrin gels to select tumor-repopulating cells (TRC) with stemness features. We found that HELLS, belonging to the 14 SRSGs, was up-regulated in ICC-TRC. And silencing HELLS significantly reduced the colony size, inhibited migration and invasion, and attenuated SASP in ICC-TRC. In summary, we provided a novel classification and risk score for ICC and uncovered a molecular mechanism via which CSLCs could obtain an active SASP.

Cancer stem cells (CSCs) are considered to play a key role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). However, little is known about lipid metabolism reprogramming in PDAC CSCs. Here, we assigned stemness indices, which were used to describe and quantify CSCs, to every patient from the Cancer Genome Atlas (TCGA-PAAD) database and observed differences in lipid metabolism between patients with high and low stemness indices. Then, tumor-repopulating cells (TRCs) cultured in soft 3D (three-dimensional) fibrin gels were demonstrated to be an available PDAC cancer stem-like cell (CSLCs) model. Comprehensive transcriptome and lipidomic analysis results suggested that fatty acid metabolism, glycerophospholipid metabolism, and, especially, the sphingolipid metabolism pathway were mostly associated with CSLCs properties. SPHK1 (sphingosine kinases 1), one of the genes involved in sphingolipid metabolism and encoding the key enzyme to catalyze sphingosine to generate S1P (sphingosine-1-phosphate), was identified to be the key gene in promoting the stemness of PDAC. In summary, we explored the characteristics of lipid metabolism both in patients with high stemness indices and in novel CSLCs models, and unraveled a molecular mechanism via which sphingolipid metabolism maintained tumor stemness. These findings may contribute to the development of a strategy for targeting lipid metabolism to inhibit CSCs in PDAC treatment.

Cancer stem‐like cells (CSLC) are considered a major contributor to the development and progression of hepatocellular carcinoma (HCC). Previous studies indicated that CSLC are characterized by resistance to ferroptosis, a type of lipid peroxidation‐dependent cell death. Here, we identified a set of ferroptosis‐related stemness genes (FRSG) and found that these genes may be involved in immune infiltration in HCC. A four‐FRSG ( CDKN2A , GABARAPL1 , HRAS , RPL8 ) risk model with prognostic prediction was constructed by a Cox analysis in HCC. Among these four genes, GABARAPL1 was downregulated in HCC tumor‐repopulating cells (TRC; a type of CSLC). Its downregulation decreased the sensitivity of HCC TRC to erastin‐ or sorafenib‐triggered ferroptosis. Together, we uncovered a molecular mechanism via which CSLC could achieve tolerance to ferroptosis. Further studies may provide potential therapeutic strategies targeting CSLC in HCC.