Chronic d-galactose (d-gal) injection is an experimental model of accelerated aging in rodents. However, the cardiovascular phenotypes of this model have been poorly characterized, especially as they relate to sex differences. The goal of this study was to investigate the cardiovascular effects of chronic d-gal injection in male and female C57BL/6 mice and the impact of HO-1 induction or inhibition in this model. Forty-eight 8-week-old male and female C57BL/6 mice were divided randomly into four groups (n = 6): control, d-gal, d-gal + CoPP, and d-gal + ZnBG. Body weight, echocardiography, blood pressure measurement, Doppler ultrasound, echoMRI, micro-CT, histopathology, and protein analysis were performed. Our results show a strong sexual dimorphism in the cardiovascular effects of d-gal treatment and the effects of HO-1 induction or inhibition. Male mice were found to be more prone to systolic dysfunction and oxidative stress upon d-gal treatment and benefited more from the protective effects of HO-1 induction. Female mice were found to be protected from the cardiac effects of d-gal treatment yet were more prone to the effects of HO-1 inhibition. Our results demonstrate a sexually dimorphic response to the cardiovascular effects of d-gal treatment and alterations in HO-1.

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1.

Prolonged activation of the hypothalamic-pituitary-adrenal axis results in excessive secretion of the glucocorticoid (GC) hormone cortisol, which contributes to weight gain, increased appetite, and inflammation. GCs are essential in regulating stress responses and suppressing immune functions. They bind to the GC receptor and influence gene expression through transcriptional mechanisms. Sustained elevation of GC levels may lead to GC resistance, thereby contributing to inflammation, adiposity, and insulin resistance, which negatively impact the hepatic, cardiovascular, and renal systems. This condition is referred to as cardiovascular-kidney-metabolic (CKM) syndrome. The notable pathologies associated with GC resistance and CKM syndrome are discussed, with particular emphasis on CKM staging and potential therapeutic strategies for individuals with cardiometabolic dysfunction.

Hepatic nerves have an underexplored role in liver function. The global prevalence of liver disease has reached unprecedented levels, with over 1.6 billion individuals affected by metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive understanding of these liver disease mechanisms is essential for identifying the aetiologies of such conditions. Studies from the past 5 years suggest that hepatic nerves might influence the progression of MASLD to metabolic dysfunction-associated steatohepatitis and hepatocellular carcinoma. As MASLD advances, hepatic sympathetic activity increases while hepatic sympathetic innervation diminishes. Conversely, both parasympathetic and sympathetic innervation might contribute to hepatic fibrosis and liver dysfunction. This Review examines the function of hepatic neurons, their modulation by metabolic disease and the potential to target these mechanisms to develop novel treatments for liver diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly associated with the development of cardiovascular disease (CVD); however, the mechanisms responsible are currently unknown. We have developed a model of MASLD due to the loss of hepatocyte peroxisome proliferator-activated receptor α (PPARαHEPKO). We found that plasma beta-hydroxybutyrate (BHOB) levels were significantly reduced in PPARαHEPKO mice and aimed to investigate the therapeutic potential of restoring BHOB levels in the development of CVD in these mice. Thirty-week-old PPARαHEPKO and control PPARαFL/FL mice were randomized to receive 1,3 butanediol (1,3-BDO), a precursor of BHOB, in drinking water for 6 weeks. 1,3-BDO treatment resulted in a significant increase in plasma BHOB levels, a significant decrease in mean arterial blood pressure, improvement in systolic and diastolic function, a decrease in vascular stiffness, and improved exercise performance in PPARαHEPKO mice. 1,3-BDO treatment did not alleviate hepatic steatosis in PPARαHEPKO mice; however, it improved plasma cholesterol levels and decreased cardiac lipid accumulation, fibrosis, and apoptosis. 1,3-BDO treatment also resulted in a significant increase in cardiac AMP-activated protein kinase (AMPK) levels. Increasing plasma BHOB levels reverses CVD in our mouse model of MASLD. A similar approach could be an effective strategy for preventing the development of CVD in patients with human MASLD.

Bilirubin, historically recognized solely as a waste product of heme catabolism, has recently gained attention for its potential protective role in the cardiovascular system. Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the heart against oxidative stress, ischemia-reperfusion injury, and the progression of cardiovascular diseases, such as heart failure. As an endogenous hormone, bilirubin activates peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that controls energy balance and lipid metabolism. Moderately elevated circulating bilirubin levels have been associated with a reduced risk of coronary artery disease, heart failure, and myocardial infarction; however, the mechanisms underlying bilirubin's protective effects remain incompletely understood. Conversely, the gut microbiota's metabolism of bilirubin to urobilin is detrimental, given urobilin's association with cardiometabolic dysfunction. The therapeutic potential of bilirubin in the management of cardiovascular disease is becoming increasingly apparent, supported by preclinical research and emerging technologies that enhance bilirubin delivery via nanoparticles and methods to elevate plasma bilirubin levels. Collectively, these scientific advancements position bilirubin as a promising, biologically plausible endogenous therapeutic for the prevention and treatment of heart disease.

To evaluate the crosstalk between the liver, heart, and kidneys in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), highlighting the distinct regulatory roles of non-traditional hepatokines, and to assess shared therapeutic targets and molecular mechanisms driving cardiorenal complications in MASLD patients. Emerging evidence highlights that hepatic lipid accumulation drives cardiac damage, which manifests as adverse remodeling, diastolic dysfunction, and coronary microvascular dysfunction. These abnormalities are mediated primarily by systemic lipotoxicity, inflammation of epicardial adipose tissue, and a pro-thrombotic environment. Mechanistically, altered hepatokine signaling mediates systemic cross-talk. Specifically, the downregulation of cardioprotective and renoprotective brain-derived neurotrophic factor (BDNF) and the dual metabolic roles of nerve growth factor (NGF), fibroblast growth factor (FGF) 19, and FGF21 accelerate the progression of both heart failure and chronic kidney disease (CKD). Concurrently, metabolic therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and peroxisome proliferator-activated receptor (PPAR) agonists demonstrate significant efficacy in ameliorating steatosis, inflammation, and overall metabolic outcomes. MASLD acts as a systemic driver of multi-organ dysfunction within the cardio-renal-hepatic axis. Profiling specific hepatokine signatures offers a promising frontier for identifying novel therapeutic targets and biomarkers of disease acceleration. Furthermore, while current metabolic therapies show remarkable potential, rigorous clinical testing remains critical to definitively determine whether their cardiovascular and renal benefits stem from direct tissue-specific protective mechanisms or secondary metabolic improvements.

Polymorphism in the patatin-like phospholipid domain-containing protein 3 ( Pnpla3 ) is linked to metabolic dysfunction-associated steatotic liver disease (MASLD). In the US, >30% of MASLD patients have the most common type of Pnpla3 polymorphism in which methionine is substituted for isoleucine at the 148 region ( Pnpla3 I148M ). Also, in MASLD patients, cardiovascular disease (CVD) is the leading cause of death. Since Pnpla3 is mainly expressed in the liver and kidney, clinical studies have shown that Pnpla3 I148M polymorphism increases the incidence of chronic kidney disease (CKD) independent of MASLD or any other co-morbidities. Thus the goal of our study was to determine the effect of Pnpla3 I148M polymorphism in mice on renal and cardiovascular function using an endogenous Pnpla3 I148M knock-in mouse model. Male (M) and female (F) Pnpla3 I148M and C57BL6/J (control) mice at 16 weeks of age were either switched to a high sucrose diet (HSD) or left on a normal sucrose diet (NSD) for 8 extra weeks (n=6-11/group). Glomerular filtration rate (GFR) studies were performed at week 6 of diet using transdermal GFR probe and echocardiography at week 8 using Vevo Sonics imaging system. Pnpla3 I148M polymorphism increased liver triglyceride in HSD-fed (M: 0.3±0.0 vs 0.5±0.2 mM, F: 0.4±0.0 vs 0.5±0.0 mM p<0.05) but not in NSD-fed mice (M: 0.2±0.0 vs 0.2±0.0 mM, F: 0.2±0.0 vs 0.3±0.0 mM). Pnpla3 I148M polymorphism also increased end-systolic volume (M NSD: 34.1±4.2 vs 51.0±5.5 µl, M HSD: 18.8±2.3 vs 41.9±2.8 µl p<0.05); (F NSD: 16.9±2.3 vs 31.6±4.3 µl, F HSD: 13.8±1.8 vs 27.7±3.1 µl p<0.05) and end-systolic diameter (M NSD: 2.9±0.1 vs 3.6±0.1 mm, M HSD: 2.3±0.1 vs 3.4±0.1 mm p<0.05); (F NSD: 2.1±0.2 vs 2.9±0.2 mm, F HSD: 1.8±0.2 vs 2.9±0.1 mm p<0.05). Ejection fraction was decreased in Pnpla3 I148M mice (M NSD: 51.2±2.7 vs 40.3±1.9 %, M HSD: 53.3±2.2 vs 36.3±1.4 % p<0.05); (F NSD: 59.1±3.7 vs 45.6±3.5 %, F HSD: 55.2±2.5 vs 43.5±2.9 % p<0.05) along with fractional shortening (M NSD: 26.2±1.7 vs 16.3±1.3 %, M HSD: 20.3±0.9 vs 14.7±1.4 % p<0.05); (F NSD: 28.9±2.5 vs 19.5±1.8 %, F HSD: 23.7±1.9 vs 18.2±1.7 % p<0.05). A high sucrose diet caused further alterations in cardiovascular morphology and function in Pnpla3 I148M mice, namely end-diastolic volume, end-diastolic diameter, cardiac output, left carotid and abdominal aorta resistive index. Assessment of renal function and injury showed that NSD-fed and female HSD-fed Pnpla3 I148M mice exhibit hyperfiltration (M NSD: 919.6±32.5 vs 1281.9±49.2 µl/min/100gBW, M HSD: 931.2±80.8 vs 918±53.2 µl/min/100gBW p<0.05); (F NSD: 955.4±83.0 vs 1852.8±179.2 µl/min/100gBW, F HSD: 1033.7±74.6 vs 1583.0±139.1 µl/min/100gBW p<0.05). Yet, both male and female HSD-fed Pnpla3 I148M mice had increased albumin to creatinine ratio (M NSD: 0.2±0.0 vs 0.2±0.0 %, M HSD: 0.3±0.1 vs 0.6±0.1 p<0.05); (F NSD: 0.2±0.0 vs 0.2±0.0 %, F HSD: 0.3±0.0 vs 0.5±0.1 p<0.05). These findings show that Pnpla3 I148M polymorphism can lead to renal and cardiac dysfunction, which exacerbate on a high sucrose diet, and that understanding the mechanism of dysfunction can provide novel targets for MASLD, CVD in MASLD and CKD patients with Pnpla3 I148M polymorphism. Ongoing studies will investigate the mechanism of hyperfiltration and its effect on blood pressure regulation in Pnpla3 I148M mice. This work was supported by the NIDDK 1R01DK121748-01A1 (DES) and the NIGMS P20GM104357-02 P30GM149404 and P20GM144041 awards This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Alteration in renal function has long been known to be a consequence of liver disease. However, the mechanisms by which the liver can regulate kidney function under basal conditions and in response to liver disease have yet to be fully understood. The liver is a complex organ capable of producing metabolites, including ketones, bile acids, and hepatokines such as fibroblast growth factor 21. Alterations in the hepatic production of these metabolites and hormones can significantly affect renal function and may play a crucial role in the development of kidney disease. The goal of this review is to summarize the mechanisms by which liver-derived metabolites and hepatokines regulate kidney function in health and disease.

Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.

BACKGROUND:Increased circulating bilirubin attenuates angiotensin (Ang) II-induced hypertension and improves renal hemodynamics. However, the intrarenal mechanisms that mediate these effects are not known. The goal of the present study was to test the hypothesis that bilirubin generation in the renal medulla plays a protective role against Ang II-induced hypertension. METHODS:Twenty-week-old male C57Bl/6J mice were implanted with intrarenal medullary interstitial (IRMI) catheters following unilateral nephrectomy. After this time, biliverdin IXα was specifically infused into the kidney (3.6 mg/day) for 3 days before implantation with an osmotic minipump delivering Ang II (1,000 ng/kg/min). BP was recorded for 3 days, 1 week after minipump infusion, in conscious mice. To further explore the antihypertensive role of renal medullary bilirubin generation, mice with specific deletion of biliverdin reductase-A (Blvra) in the thick ascending loop of Henle were generated. At 20 weeks, BlvraTALHKO and control mice (Blvrafl/fl) were infused with Ang II for 2 weeks. RESULTS:IRMI infusion of biliverdin significantly decreased blood pressure compared with mice infused with vehicle (118 ± 4 vs. 158 ± 2 mmHg, p < 0.05). Angiotensin-II infusion resulted in significantly higher blood pressure measured in conscious mice 7 days after implantation in BlvraTALHKO as compared to Blvrafl/fl mice (152 ± 2 vs. 140 ± 3 mmHg, P < 0.05). CONCLUSIONS:Altogether, these findings show that medullary bilirubin and biliverdin reductase can improve hypertension and that mechanisms that increase bilirubin and biliverdin reductase in the renal medulla could be an effective approach to treat hypertension.

The journal retracts the article "Cold Press Nigella Sativa oil standardized to 3%, thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation and Insulin Resistance via Conversion of White to Beige Fat in Mice" [...].

IntroductionDegenerin proteins, such as βENaC and ASIC2, have been implicated in cardiovascular function. However, their role in metabolic syndrome have not been studied. To begin to assess this interaction, we evaluated the impact of a high fat diet (HFD) on mice lacking normal levels of ASIC2 (ASIC2-/-) and βENaC (βENaCm/m).MethodsTwenty-week-old male and female mice were placed on a 60% HFD for 12 weeks. Body weight was measured weekly, and body composition by non-invasive ECHO MRI and fasting blood glucose were measured at 0, 4, 8 and 12 weeks. A glucose tolerance test was administered after 12 weeks. Differences between ASIC2-/-/βENaCm/m and WT groups were compared using independent t-tests or ANOVA where appropriate within each sex. Data are presented as mean ± SEM and ASIC2-/-/βENaCm/m vs. WT. ResultsAt 20 weeks of age, ASIC2-/-/βENaCm/m mice (n=9F/10M) weighed less and gained less weight than WT (n=12F/16M). Total body fat and lean body masses were reduced in female and male ASIC2-/-/βENaCm/m mice. Total body fat and lean body masses as % control were identical at the end of 12 weeks. Fasting blood glucoses were lower in female and male ASIC2-/-/βENaCm/m vs. WT mice after 12 weeks HFD. The area under the curve for the glucose tolerance test was reduced in female and tended (p=.079) to decrease in male ASIC2-/-/βENaCm/m. Plasma leptin and insulin were reduced in female and male ASIC2-/-/βENaCm/m vs. WT mice. Plasma insulin in female ASIC2-/-/βENaCm/m mice remained unchanged throughout the HFD period. Liver and liver fat masses, as well as percent liver fat, were reduced in both female and male ASIC2-/-/βENaCm/m mice after HFD. Plasma triglycerides, cholesterol, LDL- and HDL-cholesterols were markedly improved in male and/or female ASIC2-/-/βENaCm/m following the HFD.DiscussionThese novel findings suggest that loss of ASIC2 and βENaC offer a significant protection against HFD-induced metabolic syndrome.

Over the past 55 years, the heme oxygenase (HO) system has emerged as a pivotal player in a myriad of cellular, tissue, and integrative physiological processes [...]

Abstract The leading cause of death among patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte‐specific peroxisome proliferator‐activated receptor alpha knockout (PparaHepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis‐induced cardiac dysfunction in PparaHepKO mice. Experiments were performed in 30‐week‐old PparaHepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 μm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase‐3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro‐caspase‐3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B‐cell lymphoma protein 2‐associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B‐cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in PparaHepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

The global prevalence of obesity and its related comorbidities, including diabetes and metabolic dysfunction associated fatty liver disease (MAFLD), are on the rise. For unknown reasons, serum bilirubin levels are negatively correlated with obesity, diabetes, and MAFLD. We have previously generated pegylated bilirubin nanoparticles (PEGBR) and found they have therapeutic potential in preclinical models of diet-induced obesity and MAFLD. Bilirubin has long been known to function as an antioxidant. However, our lab has previously identified its hormonal function by binding to and activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa). It is unknown whether the beneficial effects of PEGBR are due to its antioxidant or hormonal function. To determine this, we induced obesity and MAFLD in female and male hepatocyte-specific PPARa knockout mice (PparaHepKO) and floxed (Pparaflox) control mice by a high-fat diet for 30 weeks. The mice were then treated with vehicle or PEGBR (30 mg/kg) for six weeks while remaining on the high-fat diet. In female Pparaflox mice, PEGBR significantly lowered body weight, but not in the female PparaHepKOmice. A similar trend was seen in the male Pparaflox mice but was not statistically significant. We found that PEGBR significantly reduced hepatic fat mass and triglycerides in the Pparaflox mice but not in the PparaHepKO mice in both sexes. We then performed mass-spectroscopy to analyze the hepatic lipid composition. In the male mice there was an 93.6% reduction in the number of lipid species that were significantly lowered by PEGBR in the PparaHepKO mice compared to the Pparaflox mice. While in the female PparaHepKO mice, there was a 2.7% reduction in the number of lipid species significantly decreased by PEGBR compared to Pparaflox controls. Plasma lipids and metabolites were quantified using NMR and we found that male Pparaflox mice had an increase in plasma high-density lipoprotein cholesterol and a decrease in very-low-density particle number with PEGBR, but this was not seen in the male PparaHepKO or female mice. PEGBR also significantly reduced fasting blood glucose and insulin levels only in the Pparaflox mice of both female and male mice. Overall, the data indicates bilirubin's hormonal function through PPARa is responsible for the protective effects of bilirubin on obesity, MAFLD, and glucose tolerance. This study also confirms the therapeutic potential of bilirubin nanoparticles for obesity and its associated comorbidities. This work was supported by the National Institutes of Health F31HL170972 (Z.A.K.) and R01DK121797 (T.D.H.J.) and R01DA058933 (T.D.H.J.).

The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.

Sex differences are a complex and crucial variable in developing and progressing metabolic and cardiovascular disease pathophysiology and clinical outcomes. The female sex, compared to the male sex, is protected from metabolic disturbances and their resulting cardiovascular events. However, the peculiar life phases associated with females, such as puberty, pregnancy, and premenopausal and menopausal stages, are all associated with different risks for the development of cardiovascular disease (CVD). Metabolic dysfunction-associated steatotic liver disease (MASLD), a condition of hepatic steatosis, and at least one feature of metabolic syndrome is associated with an increased risk of cardiovascular events. The risk of MASLD and its progression to the development of CVD differs between men and women. Differences in several factors, including formyl peptide receptor (FPR) 2, adipose tissue distribution, liver pyruvate kinase (LPK), and ketone body production, may underlie the sex differences in the risk of development of MASLD-induced CVD. Understanding the specific risk factors involved in the development and progression of MASLD between the sexes is crucial. This knowledge will provide important insights into the mechanisms responsible for its cardiovascular complications and can potentially lead to therapeutics targeted explicitly for each sex, offering new hope in the fight against MASLD-induced CVD.