Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.

Metaflammation is characteristic of chronic metabolic inflammation, associated with increased risk of development of metabolic dysfunction-associated steatotic liver disease (MASLD). Palmitoylation of Myeloid differentiation factor 88 (MyD88) adaptor protein mediates biologically important signal transduction pathways in inflammatory responses. However, the molecular mechanisms underlying MyD88 palmitoylation contributes to lipid-induced metaflammation in the progression of MASLD is not completely understood. In this study, an increment of MyD88 palmitoylation was observed in the livers of high-fat diet fed mice, accompanied by increased lipid accumulation and an inflammatory response. Inhibition of MyD88 palmitoylation attenuated the inflammation and hepatic steatosis in HFD-induced mice. Mechanistically, palmitoylation of MyD88 activated NF-κB-p65 and p38 MAPK signals in a selenoprotein K (SelK)-DHHC6 palmitoyltransferase complex dependent pathway. Intervention of SelK SH3 binding domain reduced the palmitoylation level of MyD88 by inhibiting the interaction between SelK and DHHC6. Our findings suggest that MyD88 palmitoylation regulates the metabolic disorder and metaflammation through SelK/DHHC6-dependent pathway, cooperatively. Inhibition of MyD88 palmitoylation and SelK SH3 binding domain may represent a new therapeutic strategy for treatment of MASLD progression.

Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.

Durable responses to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) was performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a phase 2 clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2, mainly derived from immunosuppressive myeloid-derived suppressor cells (MDSCs). In particular, the high circulating IL-8 level was strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of the IL-8/CXCR2 pathway significantly abrogated MDSC trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcomes also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response but it also provides a proof of concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.

Cancer immunotherapy has improved the survival of a subset of patients by harnessing the power of the immune system to find and destroy malignant cells. The immune system also protects the host by destroying developing premalignant and malignant tumors. Advancing our knowledge of premalignant immunity and immune changes seen in lesions that develop into invasive cancer versus those that regress offers an exciting opportunity to leverage the immune system for immune prevention and immune interception of premalignancy. Understanding the immune environment of premalignant lesions and how chronic inflammation plays a central role in the evolution of premalignancy is essential for developing effective immunoprevention and immune interceptions. Factors such as host genomics and environmental factors that affect premalignant immunity and the outcome of advanced cancers are equally important in determining the response to immunotherapy. The broad use of antibiotics and factors such as obesity can disrupt a healthy gut microbiome and drive chronic inflammation that suppresses preventive immunity or the antitumor immune response required for successful immunotherapy in advanced cancers. Modifiable lifestyle factors such as diet, obesity, smoking, and stress should be considered in designing immune prevention and interception studies, as well as for patients who receive immunotherapy for advanced cancer treatment. Other factors, such as the overall immune health of patients and existing comorbidities, affect both premalignant immunity and response to immunotherapy and, therefore, should be considered in managing patients with or without cancer. The Society for Immunotherapy of Cancer previously developed an overarching manuscript regarding the challenges and opportunities that exist in cancer immunotherapy, and this manuscript serves as an in-depth follow-up regarding the topics of premalignant immunity, immune interception, and immunoprevention, and the impact of the host on responding to immunotherapy.

Hepatocellular carcinoma (HCC) represents the most prevalent form of liver cancer. Despite notable advancements in therapeutic strategies, HCC continues to pose significant public health challenges due to its rising incidence and high mortality rates worldwide. Selenium is an essential trace element that playing a critical role in human health. Recent studies have highlighted its potential preventive and therapeutic benefits in the context of HCC. However, some in vitro and in vivo investigations have yielded inconsistent results, and the mechanisms by which selenium influences HCC are still not completely clear. This review begins by providing an extensive evaluation of the effects and mechanisms of selenium on the primary risk factors associated with HCC, including viral infections, metabolic abnormalities, and lifestyle factors. Subsequently, we outline the roles and mechanisms by which selenium influences the proliferation, metastasis, and immune microenvironment of HCC. Finally, we emphasize the imperative for further investigation into the optimal dosage and forms of selenium, as well as its effects on the HCC microenvironment, to inform the development of effective clinical strategies. This review thus provides a foundational framework for the potential clinical application of selenium in the treatment of HCC.

Obesity is associated with liver depletion of ω-3 polyunsaturated fatty acids (ω-3 PUFAS) promoting steatosis and inflammation, whose levels are maintained by diet or biosynthesis involving Δ-5D, Δ-6D desaturases and elongases.

We aimed to assess Δ-5D and Δ-6D activities in liver and brain from mice fed a control diet (CD) or high-fat diet (HFD) for four to sixteen weeks.

HFD led to (1) an early (4 weeks) enhancement in liver Δ-5D, Δ-6D, and PPAR-α activities, without changes in oxidative stress, liver damage or fat accumulation; (2) a latter progressive loss in hepatic desaturation with insufficient compensatory increases in mRNA and protein expression, leading to ω-3 PUFA depletion, PPAR-α down-regulation reducing FA oxidation, and liver steatosis with enhancement in lipogenesis; and (3) brain ω-3 PUFA depletion after 12 to 16 weeks of HFD feeding.

In conclusion, the brain-liver axis is drastically affected by obesity in a time dependent fashion.

A high-fat diet (HFD) is often associated with hepatic lipid metabolism disorders, leading to dysfunction in multiple body systems. Ginsenosides derived from Panax ginseng have been reported to possess potential effects in ameliorating lipid metabolism disorders; however, their underlying mechanisms remain insufficiently explored. This study aims to investigate the bioactivities of ginsenosides in combating lipid metabolism disorders and obesity, with a focus on their mechanisms involving the cholesterol metabolism signaling pathway and gut microbiota. Our results demonstrated that ginsenoside treatment significantly reduced overall body weight, body weight changes, liver weight, and eWAT weight, as well as alleviated hepatic steatosis and dyslipidemia in HFD-fed rats, without affecting food intake. These effects were dose-dependent. Furthermore, 16S rRNA sequencing revealed that ginsenosides significantly increased the relative abundance of Akkermansia muciniphila, Blautia, Eisenbergiella, Clostridium clusters XI, XVIII, and III, while decreasing the relative abundance of Clostridium subcluster XIVa and Dorea. In addition, ginsenoside treatment significantly regulated the expression of hepatic genes and proteins involved in the cholesterol metabolism signaling pathway (FXR, CYP7A1, CYP7B1, CYP27A1, ABCG5, ABCG8, Insig2, and Dhcr7), potentially inhibiting hepatic cholesterol biosynthesis while promoting cholesterol transport to HDL and its excretion via bile and feces. Notably, levels of 7-dehydrocholesterol (7-DHC) and 27-hydroxycholesterol (27-OHC) were reduced, while 5β,6β-epoxycholesterol (5,6β-epoxy) levels were elevated following ginsenoside treatment, indicating significant modulation of oxysterols by ginsenosides. Moreover, bile acid enterohepatic circulation was regulated through the enhancement of hepatic FXR-CYP7A1 signaling and intestinal FXR-FGF15 signaling in HFD-fed rats treated with ginsenosides, which was closely linked to gut microbiota composition. Collectively, our findings suggest that ginsenosides alleviate hepatic lipid metabolism disorders by modulating gut microbiota and the cholesterol metabolism signaling pathway in HFD-fed rats.

Shear wave (SW) elastography is used to evaluate metabolic dysfunction-associated steatotic liver disease (MASLD) pathophysiology. Increased elasticity due to fibrosis and increased viscosity due to necrosis and inflammation affect SW. Assessing fibrosis, the most prognostically relevant pathology, is critical. Viscosity is evaluated using the dispersion slope (DS); however, cut-off values that affect SW values are unclear. We compared the ultrasound imaging parameters (SW for viscoelasticity; DS for viscosity) with pathological findings.

Patients (n = 159) who underwent liver biopsy and SW and DS assessments at our hospital were included. Fibrosis stage and inflammation grade cut-off values were calculated from SW, DS, and liver biopsy results using receiver operating characteristic curves. Cases in which liver biopsy results were inconsistent with SW results were used to determine the effect of viscosity on SW values. DS was examined in the Correct and Incorrect Diagnosis groups, which were categorized based on the concordance between SW and liver biopsy results. Dispersion slope cut-off values between the two groups were calculated.

Fibrosis stage cut-off values by SW (m/s) were: ≥F2, 1.62; ≥F3, 1.74; and F4, 1.97. Inflammation grade cut-off values by DS (m/s/kHz) were: ≥A1, 11.6; ≥A2, 14.5; and A3, 16.1. The Correct/Incorrect Diagnosis groups had 25/70 patients. The DS cut-off value for both groups was 13.2 m/s/kHz.

Shear wave and DS are useful for evaluating liver fibrosis and inflammation in MASLD. For DS > 13.2 m/s/kHz, SW may be affected by the increased viscosity owing to inflammation. In such patients, caution should be used when determining/interpreting values.

Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.

Pancreatic ß-cells are glucose sensors in charge of regulated insulin delivery to the organism, achieving glucose homeostasis and overall energy storage. The latter function promotes obesity when nutrient intake chronically exceeds daily expenditure. In case of ß-cell failure, such weight gain may pave the way for the development of Type-2 diabetes. However, the causal link between excessive body fat mass and potential degradation of ß-cells remains largely unknown and debated. Over the last decades, intensive research has been conducted on the role of lipids in the pathogenesis of ß-cells, also referred to as lipotoxicity. Among various lipid species, the usual suspects are essentially the non-esterified fatty acids (NEFA), in particular the saturated ones such as palmitate. This review describes the fundamentals and the latest advances of research on the role of fatty acids in ß-cells. This includes intracellular pathways and receptor-mediated signaling, both participating in regulated glucose-stimulated insulin secretion as well as being implicated in ß-cell dysfunction. The discussion extends to the contribution of high glucose exposure, or glucotoxicity, to ß-cell defects. Combining glucotoxicity and lipotoxicity results in the synergistic and more deleterious glucolipotoxicity effect. In recent years, alternative roles for intracellular lipids have been uncovered, pointing to a protective function in case of nutrient overload. This requires dynamic storage of NEFA as neutral lipid droplets within the ß-cell, along with active glycerolipid/NEFA cycle allowing subsequent recruitment of lipid species supporting glucose-stimulated insulin secretion. Overall, the latest studies have revealed the two faces of the same coin.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

Obesity is a global health issue that is intricately linked to the development and progression of chronic liver disease (CLD). This bidirectional connection, coupled with the obesity paradox (OP), presents a management dilemma. The established influence of obesity on the development and progression of chronic liver disease (CLD) is surpassed by the liver's impact on the onset and advancement of obesity. Patients with CLD always experience increased energy expenditure, reduced appetite, and low protein synthesis, all of which might lead to weight loss. However, metabolic disturbances, hormonal imbalances, inflammatory signaling, immobility, drugs, and alterations in nutrient metabolism can contribute to the development and exacerbation of obesity. Despite the propagation of the OP concept, none of the guidelines has changed, recommending being overweight. Research bias and confounders might be the lifebuoy explanation. Additionally, overlooking the lethal morbidities of obesity for survival benefits full of suffering seems to be an illogical idea. Therefore, rather than endorsing an overweight status, emphasis should be placed on improving cardiorespiratory fitness and preventing sarcopenia to achieve better outcomes in patients with CLD. Accordingly, the complex interplay between obesity, CLD, and the concept of OP requires a sophisticated individualized management approach. Maximizing cardiorespiratory fitness and mitigating sarcopenia should be considered essential strategies for attaining the most favourable outcomes in patients with chronic liver disease (CLD).

Incidence rates of liver cancer have increased worldwide in recent decades, making it a major public health problem globally. Obesity can be caused by multiple factors and promotes the development of liver cancer in many ways. Although the research on the association between obesity and liver cancer was previously explored, we first employed bibliometrics to analyze the current research status. From 2012 to 2023, the Web of Science Core Collection database was searched for studies regarding the association between obesity and liver cancer. To evaluate worldwide trends and research hotspots in this topic, bibliometric analysis tools such as VOSviewer, CiteSpace, and R Package were employed. Altogether 233 eligible publications, consisting of 167 articles and 66 reviews, were analyzed. The yearly number of publications and average citation numbers have increased over the last 11 years, particularly the last 6 years. The great majority of published articles on this topic originated from the United States (n = 89, 38.20%), followed by China (n = 60, 25.75%), and England (n = 23, 9.87%). In this subject's research, American scholars embodied considerable production, great prominence, and high academic influence. The most cited article was Yoshimoto, S et al of Japan Science and Technology Agency published in 2013 with a citation number of 1410. We apply bibliometric analysis for the first time in this field, expecting to help scholars efficiently and effectively retrieve the association between obesity and liver cancer.

Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH-HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g-1, weekly) for 24 weeks. TACE activity, TNF-α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF-α, which upregulated AATF, a key molecular driver of MASH-HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF-mediated inflammation, fibrosis, and oncogenesis in MASH-HCC, offering a potential target for therapeutic intervention.

Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression. In response to inflammatory stimuli, neutrophils become activated, releasing neutrophils extracellular traps (NETs) for the capture and eradication of pathogens, a phenomenon termed NETosis. With a deeper understanding of NETs, there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies, especially concerning tumor reactions to chemotherapy, radiation therapy (RT), and immunotherapy. This review summarizes the roles of NETs in the tumor microenvironment (TME) and their mechanisms of neutrophil involvement in the host defense. Additionally, it elucidates the mechanisms through which NETs promote tumor progression and their role in cancer treatment resistance, highlighting their potential as promising therapeutic targets in cancer treatment and their clinical applicability.

Obesity is often associated with a chronic, low-grade inflammatory state affecting the entire body. This sustained inflammatory state disrupts the coordinated communication between the periphery and the brain, which has a crucial role in maintaining homeostasis through humoural, nutrient-mediated, immune and nervous signalling pathways. The inflammatory changes induced by obesity specifically affect communication interfaces, including the blood-brain barrier, glymphatic system and meninges. Consequently, brain areas near the third ventricle, including the hypothalamus and other cognition-relevant regions, become susceptible to impairments, resulting in energy homeostasis dysregulation and an elevated risk of cognitive impairments such as Alzheimer's disease and dementia. This Review explores the intricate communication between the brain and the periphery, highlighting the effect of obesity-induced inflammation on brain function.

Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.

Inflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis.

We induced liver fibrosis in Il15-/- , Il15ra-/- and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl4). Liver fibrosis was evaluated by Sirius red and Mason's trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry.

Both Il15-/- and Il15ra-/- mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra-/- mice showed further reduction in collagen deposition compared to Il15-/- mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15-/- and Il15ra-/- mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15-/- and Il15ra-/- mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45+ immune cells and CD68+ macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice.

Our findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα.

Mulberry leaf has been recognized as a traditional Chinese medicinal plant, which was distributed throughout the Asia. The aqueous extract of mulberry leaf extract (MLE) has various biologically active components such as polyphenols and flavonoids. However, the inhibitory effect of MLE in hepatocarcinogenesis is poorly understood. In this study, we determined the role of MLE supplementation in preventing hepatocarcinogenesis in a carcinogen-initiated high-fat diet (HFD)-promoted Sprague-Dawley (SD) rat model. The rats were fed an HFD to induce obesity and spontaneous hepatomas by administering 0.01% diethylnitrosamine (DEN) in their drinking water for 12 weeks (HD group), and also to fed MLE through oral ingestion at daily doses of 0.5%, 1%, or 2%. At the end of the 12-week experimental period, the liver tumors were analyzed to identify markers of oxidative stress and antioxidant enzyme activities, and their serum was analyzed to determine their nutritional status and liver function. Histopathological analysis revealed that MLE supplementation significantly suppressed the severity and incidence of hepatic tumors. Furthermore, compared with the HFD + DEN groups, the expression of protein kinase C (PKC)-α and Rac family small GTPase 1 (Rac1) was lower in the MLE groups. These findings suggest that MLE prevents obesity-enhanced, carcinogen-induced hepatocellular carcinoma development, potentially through the protein kinase C (PKC)α/Rac1 signaling pathway. MLE might be an effective chemoprevention modality for nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis.

Sarcopenia and physical deconditioning are common complications in patients with liver cancer, which are frequently caused by insufficient physical activity and poor nutritional status, resulting in physical frailty and a significant impact on the patient's physical fitness. Notably, sarcopenia, frailty, and poor cardiopulmonary endurance have all been linked to higher mortality rates among patients with liver cancer. Exercise intervention significantly improves various health parameters in liver cancer patients, including metabolic syndrome, muscle wasting, cardiorespiratory endurance, health-related quality of life, and reduction in hepatic venous pressure gradient. However, the link between physical exercise and liver cancer is commonly overlooked. In this article, we will examine the impact of exercise on liver cancer and present the most recent evidence on the best types of exercise for various stages of liver cancer. This article also summarizes and discusses the molecular mechanisms that control metabolism and systemic immune function in tumors. In brief, physical exercise should be considered an important intervention in the prevention and treatment of liver cancer and its complications.

Liver precancerous lesions are the key to improving the efficacy of cancer treatment because of the extremely poor prognosis of HCC patients in moderate and late stages. Obesity-related HCC progression is closely related to the inflammatory microenvironment, in which macrophages are one of the major constituents. In the present study, we ask whether obesity promotes diethylnitrosamine (DEN)-induced precancerous lesions by M1 macrophage polarization. First, an association between obesity and liver precancerous lesions was determined by histopathological observations, immunochemistry and immunoblotting. The characteristics of early precancerous lesions (trabecular thickening) appeared earlier eight weeks in obese mice than in normal diet mice after DEN induction. The glutathione S-transferase placental-1 (Gstp 1) and alpha-fetoprotein (AFP) expression in obese mice after DEN induction was higher than that in the same period after DEN injection in normal diet mice. Furthermore, there was a significant increase in the total macrophage number (F4/80+) of DEN and M1 macrophage number (CD86+F4/80+) in obese mice compared with that in normal diet mice. Besides, the expressions of four pro-inflammatory factors in DEN-induced obese mice were significantly higher compared with that in normal diet mice. Additionally, angiogenesis was revealed by immunostaining assay to be associated with the inflammatory response. All the results demonstrate that obesity promotes DEN-induced precancerous lesions by inducing M1 macrophage polarization and angiogenesis.

Artificially fermented dark loose tea is a type of novel dark tea prepared via fermentation by Eurotium cristatum. The effects of artificially fermented dark loose tea on lipid metabolism are still unclear.

This study aimed to explore if artificially fermented dark loose tea has the same effects as naturally fermented dark loose tea in regulating hepatic lipid metabolism.

Thirty-six 8-wk-old male C57BL/6 mice were randomly divided into 6 treatment groups, including normal control (NC), high-fat diet (HFD), positive control (PC), Wuniuzao dark raw tea (WDT), Wuniuzao naturally fermented dark loose tea (NFLT), and Wuniuzao artificially fermented dark loose tea (AFLT) groups. The HFD, PC, WDT, NFLT, and AFLT groups were fed a HFD. The PC group was supplemented with atorvastatin (10 mg/kg). The WDT group was supplemented with WDT (300 mg/kg), the NFLT group with NFLT (300 mg/kg), and the AFLT group with AFLT (300 mg/kg).

The study compared the effect of WDT, NFLT, and AFLT on liver steatosis and gut microbiota disorder in obese mice. All 3 tea extracts reduced body weight, glucose tolerance, and serum lipid concentrations. Via sterol-regulatory element binding protein (SREBP)-mediated lipid metabolism, all 3 tea extracts alleviated hepatic steatosis in mice with obesity. Furthermore, NFLT and AFLT intervened in the abundance of Firmicutes, Bacteroidetes, Clostridia, Muribaculaceae, and Lachnospiraceae.

In mice with obesity induced by a HFD, WDT, NFLT, and AFLT may improve hepatic steatosis through an SREBP-mediated lipid metabolism. Moreover, NFLT and AFLT improved the composition of gut microbiota.

Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity.

ASGR1 deficient mice (ASGR1-/-) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration.

ASGR1-/- mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1-/- mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1-/- have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function.

ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage.

Hepatocellular carcinoma (HCC) is a serious neoplastic disease with increasing incidence and mortality, accounting for 90% of all liver cancers. Hepatitis viruses are the major causative agents in the development of HCC. Hepatitis A virus (HAV) primarily causes acute infections, which is associated with HCC to a certain extent, as shown by clinicopathological studies. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections lead to persistent liver inflammation and cirrhosis, disrupt multiple pathways associated with cellular apoptosis and proliferation, and are the most common viral precursors of HCC. Mutations in the HBV X protein (HBx) gene are closely associated with the incidence of HCC, while the expression of HCV core proteins contributes to hepatocellular lipid accumulation, thereby promoting tumorigenesis. In the clinical setting, hepatitis D virus (HDV) frequently co-infects with HBV, increasing the risk of chronic hepatitis. Hepatitis E virus (HEV) usually causes acute infections. However, chronic infections of HEV have been increasing recently, particularly in immuno-compromised patients and organ transplant recipients, which may increase the risk of progression to cirrhosis and the occurrence of HCC. Early detection, effective intervention and vaccination against these viruses may significantly reduce the incidence of liver cancer, while mechanistic insights into the interplay between hepatitis viruses and HCC may facilitate the development of more effective intervention strategies. This article provides a comprehensive overview of hepatitis viruses and reviews recent advances in research on aberrant hepatic immune responses and the pathogenesis of HCC due to viral infection.

Liver fibrosis is the critical stage in the development of chronic liver disease (CLD), from simple injury to irreversible cirrhosis. Timely detection and intervention of liver fibrosis are crucial for preventing CLD from progressing into a fatal condition. Herein, we developed iron oxide (Fe3O4) nanoparticles (IONPs) and ferulic acid (FA) coencapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), followed by surface modification with cRGD peptides (cRGD-PLGA/IOFA) for integrin-targeted clinical magnetic resonance imaging (MRI)-traceable treatment of liver fibrosis. The cRGD peptide linked on the surface of the PLGA/IOFA NPs could specifically bind to the overexpressed integrin αvβ3 on activated hepatic stellate cells (HSCs) in the fibrotic liver, enabling the high-sensitive clinical MR imaging (3 T) and precise staging of liver fibrosis. The FA encapsulated in cRGD-PLGA/IOFA showed excellent efficacy in reducing oxidative stress and inhibiting the activation of HSCs through the transforming growth factor-β (TGF-β)/Smad pathway. Notably, the IONPs encapsulated in cRGD-PLGA/IOFA NPs could alleviate liver fibrosis by regulating hepatic macrophages through the NF-κB pathway, lowering the proportion of Ly6Chigh/CD86+, and degrading collagen fibers. The FA and IONPs in the cRGD-PLGA/IOFA produced a synergistic enhancement effect on collagen degradation, which was more effective than the IONPs treatment alone. This study demonstrates that cRGD-PLGA/IOFA NPs could effectively relieve liver fibrosis by acting on macrophages and HSCs and provide a new strategy for the clinical MRI-traceable treatment of liver fibrosis.

US-born Latinos have a higher incidence of hepatocellular carcinoma (HCC) than foreign-born Latinos. Acculturation to unhealthy lifestyle behaviors and an immigrant self-selection effect may play a role. In this study, the authors examined the influence of generational status on HCC risk among Mexican American adults.

The analytic cohort included 31,377 self-reported Mexican Americans from the Multiethnic Cohort Study (MEC). Generational status was categorized as: first-generation (Mexico-born; n = 13,382), second-generation (US-born with one or two parents born in Mexico; n = 13,081), or third-generation (US-born with both parents born in the United States; n = 4914). Multivariable Cox proportional hazards regression was performed to examine the association between generational status and HCC incidence.

In total, 213 incident HCC cases were identified during an average follow-up of 19.5 years. After adjusting for lifestyle and neighborhood-level risk factors, second-generation and third-generation Mexican Americans had a 37% (hazard ratio [HR], 1.37; 95% confidence interval [CI], 0.98-1.92) and 66% (HR, 1.66; 95% CI, 1.11-2.49) increased risk of HCC, respectively, compared with first-generation Mexican Americans (p for trend = 0.012). The increased risk associated with generational status was mainly observed in males (second-generation vs. first-generation: HR, 1.60 [95% CI, 1.05-2.44]; third-generation vs. first-generation: HR, 2.08 [95% CI, 1.29-3.37]).

Increasing generational status of Mexican Americans is associated with a higher risk of HCC. Further studies are needed to identify factors that contribute to this increased risk.

Chronic inflammation in adipose tissue is thought to contribute to insulin resistance, which involves the gut microbiota. Our previous studies have demonstrated that ingestion of 1-kestose can alter the gut microbiota composition, increase cecal butyrate levels, and improve insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Additionally, we found that 1-kestose supplementation ameliorated insulin resistance in obese rat models fed a high-fat diet (HFD), although the effects of 1-kestose on the abundance of inflammation-related gene in adipose tissue and gut microbiota composition in these rats were not explored. This study aimed to investigate the impact of 1-kestose on these parameters in HFD-fed rats, compared to OLETF rats. Male Sprague-Dawley rats were divided into two dietary groups, control or HFD, for 19 wk. Each group was further subdivided to receive either tap water or tap water supplemented with 2% (w/v) 1-kestose throughout the study. We evaluated gene expression in adipose tissue, as well as short-chain fatty acids (SCFAs) levels and microbial composition in the cecum contents. 1-Kestose intake restored the increased relative abundance of tumor necrosis factor (Tnf) mRNA in adipose tissue and the reduced level of butyrate in the cecum contents of HFD-fed rats to those observed in control diet-fed rats. Additionally, 1-kestose consumption changed the composition of the gut microbiota, increasing Butyricicoccus spp., decreasing UGC-005 and Streptococcus spp., in the cecum contents of HFD-fed rats. Our findings suggest that 1-kestose supplementation reduces adipose tissue inflammation and increases butyrate levels in the gut of HFD-fed rats, associated with changes in the gut microbiota composition, distinct from those seen in OLETF rats.

The pathogenesis of metabolic syndrome (MetS) complications involves the excessive production of
reactive oxygen species, inflammation, and endothelial dysfunction. Due to Lycopene, a highly unstable structure and
its significant effects on modulating the metabolic system, there is a strong need for a formula that can increase its
stability. The aim of this study was to develop an approach for encapsulating Lycopene and investigate its effects on
inflammatory markers, oxidative stress, and liver enzymes in patients with MetS.
Materials and Methods: This study is a simple randomized, double-blind, objective-based clinical trial that involved
eighty subjects with MetS, who were equally and randomly assigned to two groups: one group received 20 mg of
Lycopene per day for 8 weeks, and the Placebo group followed the same protocol as the Lycopene group but received
a placebo instead of Lycopene. They were called Lycopene and placebo, respectively. During follow-up visits after 4
and 8 weeks, 20 ml of blood was collected for evaluation of liver enzymes and some inflammatory related markers.
Results: Prior to the assignment of volunteers to their respective groups, there were no notable differences in C-reactive
protein (CRP), serum liver enzymes, systolic and diastolic blood pressure, or pro-oxidant-antioxidant balance (PAB)
between the Lycopene and placebo groups. However, our subsequent analysis revealed a significant reduction in the
serum levels of CRP (P=0.001) and PAB (P=0.004) in the group that received Lycopene. Our encapsulated Lycopene
treatment was not associated with a significant difference in serum levels of alanine aminotransferase (ALT), aspartate
transferase (AST), or alkaline phosphatase (ALP) between our two groups.
Conclusion: This study investigated the impact of Lycopene on individuals with MetS, revealing a noteworthy
modulation effect on PAB and inflammation linked to MetS. However, no significant differences was demonstrated in
serum levels of ALT, AST and ALP between the studied group (registration number: IRCT20130507013263N3).

We aimed to examine trends in overall mortality rates for liver cancer and those within subgroups according to sex, age, aetiological factors and modifiable risk factors in China from 1990 to 2019.

The design of this study involved analysing liver cancer mortality rates in China from 1990 to 2019 using joinpoint regression analysis to identify significant changes in mortality rates. Annual percentage changes (APCs) and 95% CIs were used to quantify the magnitude of changes in mortality rates. The study also conducted subgroup analyses based on sex, age, aetiological factors and risk factors to better understand trends in liver cancer mortality rates.

The age-standardised mortality from liver cancer in China first increased from 28.12 to 31.54 deaths per 100 000 population in 1990-1996 (APC=2.1%, 95% CI: 1.5% to 2.6%), then dropped at varying rates (1996-2000, APC=-3.7%, 95% CI: -5.2% to -2.1%; 2000-2004, APC=-17.4%, 95% CI: -18.7% to -16.1%; 2004-2007, APC=-5.4%, 95% CI: -8.3% to -2.3%; and 2007-2012, APC=-1.4%, 95% CI: -2.3% to -0.4%), and began to increase again after 2012 (APC=1.3%, 95% CI: 0.9% to 1.7%). Hepatitis B and C virus infections accounted for 63% and 18% of liver cancer-related deaths, respectively, in China from 1990 to 2019. Smoking, drug use, alcohol use and elevated body mass index were the four leading risk factors for liver cancer mortality in China during the study period. Notable variations in both liver cancer mortality rates and changes in mortality rates were observed across sexes and age groups.

The age-standardised liver cancer mortality rate in China significantly decreased from 1996 to 2019. The major differences in liver cancer mortality rates and inconsistent changes in mortality rates between 1990 and 2019 merit the attention of researchers and policymakers.

FAS-mediated apoptosis of hepatocytes and aberrant TGF-β signaling are major drivers of liver fibrosis. Decreased miRNA let-7 expression in the livers of patients and animals with fibrosis suggests a mechanistic link of let-7 to hepatic fibrogenesis.

Using transient transfection we tested the effects of let-7 overexpression and TET3 siRNA knockdown on FAS and TGF-β1 expression and FAS-mediated apoptosis in human and mouse primary hepatocytes. We assessed the therapeutic activity of let-7 miRNA delivered via adeno-associated viral vectors in mouse models of carbon tetrachloride (CCl4)-induced and bile duct ligation (BDL)-induced liver fibrosis.

Let-7 decreased TGF-β1 production from hepatocytes through a negative feedback loop involving TET3. On the other hand, let-7 post-transcriptionally inhibits FAS expression, thereby suppressing hepatocyte apoptosis. Hepatic-specific delivery of let-7 miRNA mitigated liver fibrosis in both CCl4 and BDL mouse models.

Let-7 is a crucial node in the signaling networks that govern liver fibrosis progression. Let-7 and/or its derivatives may be used as therapeutic agents for liver fibrosis.

Hepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC.

Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte-specific ETV4-knockout (ETV4fl/fl, alb-cre ) and transgenic (ETV4Hep-TG ) mice and diethylnitrosamine-carbon tetrachloride (DEN-CCL4 ) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha (TNF-α) and mitogen-activated protein kinase 11 (MAPK11).

We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF-α and MAPK11. ETV4 was positively correlated with TNF-α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF-α secretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice. The protein levels of TNF-α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl, alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4 , indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4 -induced HCC, while transgenic expression of ETV4 promoted growth of HCC.

ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-α and MAPK11. Both the ETV4/TNF-α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF-α were potential prognostic markers for HCC patients.

Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer, causing many illnesses and deaths worldwide. The insidious clinical presentation, difficulty in early diagnosis, and the highly malignant nature make the prognosis of HCC extremely poor. The complex and heterogeneous pathogenesis of HCC poses significant challenges to developing therapies. Urine-based biomarkers for HCC, including diagnostic, prognostic, and monitoring markers, may be valuable supplements to current tools such as serum α-fetoprotein (AFP) and seem promising for progress in precision medicine. Herein, we reviewed the major urinary biomarkers for HCC and assessed their potential for clinical application. Molecular types, testing platforms, and methods for building multimolecule models in the included studies have shown great diversity, thus providing abundant novel tools for future clinical transformation and applications.

Overconsumption of high-fat foods increases the risk of fatty liver disease (FLD) and liver cancer with long pathogenic cycles. It is also known that the intake of the chemical poison nitrosamine and its nanopreparations can promote the development of liver injuries, such as FLD, and hepatic fibrosis, and significantly shorten the formation time of the liver cancer cycle. The present work confirmed that the coexposure of a high-fat diet (HFD) and nano-diethylnitrosamine (nano-DEN) altered the tumor microenvironment and studied the effect of this coexposure on the progression of fatty liver malignant transformation into liver cancer. Gene transcriptomics and immunostaining were used to evaluate the tumor promotion effect of the coexposure in mice. After coexposure treatment, tumor nodules were obviously increased, and inflammation levels were elevated. The liver transcriptomics analysis showed that the expression levels of inflammatory, fatty, and fibrosis-related factors in the coexposed group were increased in comparison with the nano-DEN- and high-fat-alone groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that coexposure aggravated the high expression of genes related to the carcinomatous pathway and accelerated the formation of the tumor microenvironment. The immunohistochemical staining results showed that the coexposure significantly increased the abnormal changes in proteins related to inflammation, proliferation, aging, and hypoxia in mouse liver tissues. The coexposure of high fat and nano-DEN aggravated the process of steatosis and carcinogenesis. In conclusion, the habitual consumption of pickled foods containing nitrosamines in a daily HFD significantly increases the risk of liver pathology lesions progressing from FLD to liver cancer.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis.

Gastrointestinal malignancies, including colon adenocarcinoma (COAD) and liver hepatocellular carcinoma (LIHC), remain leading causes of cancer-related deaths worldwide. To better understand the underlying mechanisms of these cancers and identify potential therapeutic targets, we analyzed publicly accessible Cancer Genome Atlas datasets of COAD and LIHC. Our analysis revealed that differentially expressed genes (DEGs) during early tumorigenesis were associated with cell cycle regulation. Additionally, genes related to lipid metabolism were significantly enriched in both COAD and LIHC, suggesting a crucial role for dysregulated lipid metabolism in their development and progression. We also identified a subset of DEGs associated with mitochondrial function and structure, including upregulated genes involved in mitochondrial protein import and respiratory complex assembly. Further, we identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) as a crucial regulator of cancer cell metabolism. Using a genome-scale metabolic model, we demonstrated that HMGCS2 suppression increased glycolysis, lipid biosynthesis, and elongation while decreasing fatty acid oxidation in colon cancer cells. Our study highlights the potential contribution of dysregulated lipid metabolism, including ketogenesis, to COAD and LIHC development and progression and identifies potential therapeutic targets for these malignancies.