Search Results (714)

Medicinal plants of the genus Atractylodes, primarily including Atractylodes lancea (Thunb.) DC., Atractylodes chinensis (DC.) Koidz., and Atractylodes macrocephala Koidz., are important traditional Chinese medicinal herbs that are widely recognized for their functions of “strengthening the spleen and drying dampness” and have traditionally been used to treat digestive and metabolic disorders. In recent years, with the increasing global burden of liver diseases, Atractylodes species have attracted growing attention for their potential pharmacological value in liver disease management due to their abundant bioactive compounds and diverse pharmacological activities. This review summarizes reported biological and hepatoprotective effects and proposed mechanisms of Atractylodes medicinal plants and their bioactive compounds in liver-related experimental models, including models relevant to MASLD, ALD, hepatic fibrosis, and HCC. Preclinical studies have reported changes in lipid metabolism, oxidative-stress-related markers, inflammatory responses, fibrotic indices, and tumor-cell phenotypes, accompanied by modulation of signaling pathways including AMPK/SIRT1, PPAR, Nrf2/HO-1, TLR4/MyD88/NF-κB, NLRP3, and TGF-β1/Smad. However, much of the mechanistic evidence is based on pathway-associated changes rather than direct compound–target validation, and clinical evidence remains limited. Overall, the available findings provide a preclinical pharmacological rationale for further investigation of Atractylodes-derived compounds in liver diseases, while their clinical efficacy and therapeutic roles remain to be established. Full article

Fatty liver hemorrhagic syndrome (FLHS) is a prevalent metabolic disease in laying hens, causing severe economic losses. A previous study showed that conjugated linoleic acids (CLA) alleviated estrogen-induced FLHS in chickens, but the mechanism remains unclear. In the present study, we found that CLA improved serum lipid homeostasis, reduced hepatic lipid accumulation, and enhanced antioxidant activity in FLHS chickens. Transcriptome analysis identified differentially expressed genes enriched in inflammatory response, lipid homeostasis, carbohydrate metabolism, and mitogen-activated protein kinase (MAPK)/peroxisome proliferator-activated receptor (PPAR)/insulin signaling pathways. Metabolome analysis detected differentially abundant metabolites enriched in bile secretion, thyroid hormone synthesis, the insulin signaling pathway, and glycerophospholipid metabolism. Integrated analyses revealed that CLA reshaped the hepatic metabolic profile by upregulating protective metabolites (such as ubiquinol) and downregulating pro-inflammatory/lipogenic metabolites (such as 15-hydroperoxyeicosa-8Z,11Z,13E-trienoate), which synergized with key gene regulation (fatty acid synthase, jun proto-oncogene, and fatty acid desaturase 2) and core pathway activity (MAPK/nuclear factor kappa-B inhibition, PPARα activation). The multi-omics study using an estradiol-induced rooster FLHS model elucidated the molecular regulatory network of CLA against hepatic steatosis and liver injury, and provided preliminary mechanistic clues for developing CLA functional additives to prevent and treat FLHS in commercial laying hens. Full article

Pancreatic β cells require tightly controlled cholesterol distribution to maintain glucose sensing, insulin-granule trafficking, and regulated exocytosis. ATP-binding cassette transporter A1 (ABCA1) exports cellular cholesterol and phospholipids to lipid-poor apolipoprotein A-I and is a central component of β-cell cholesterol homeostasis. β-cell-specific Abca1 deletion causes cholesterol accumulation and impaired glucose-stimulated insulin secretion, whereas human studies of rare ABCA1 loss-of-function mutations have reported heterogeneous secretory phenotypes. Endocrine, metabolic, inflammatory, lipoprotein, and post-transcriptional signals regulate pancreatic ABCA1. Exendin-4 activates CaMKK/CaMKIV/PREB-dependent transcription, insulin-like growth factor-1 acts through PI3K/Akt/FoxO1 signaling, and pemafibrate increases ABCA1 through PPAR-α-dependent regulation in experimental models. Conversely, angiotensin II, tumor necrosis factor-α, oxidized low-density lipoprotein, and N-methyl-D-aspartate suppress ABCA1 through distinct or partially convergent pathways, while miR-33a directly suppresses ABCA1 in human and mouse islets. β-cell function depends on the balance among LDLR-dependent cholesterol uptake, PCSK9-mediated receptor regulation, intracellular sterol trafficking and esterification, ABCG1-dependent handling, and ABCA1-dependent export rather than on total cellular cholesterol alone. Although several regulator-specific mechanisms remain preclinical and await independent replication, this review integrates these pathways and discusses their nutritional and translational relevance in type 2 diabetes. Full article

This study examined the effects of the trans-resveratrol (Res) and l-carnitine (l-Car) complex (RC) on mice genetically resistant to obesity. Male DBA/2J mice received low (RCl, 25/300 mg/kg BW) or high (RCh, 50/600 mg/kg BW) doses of the RC for 64 days in a control diet (CD) or a high-fat-high-carbohydrate diet (HFCD). Differential expression (DE) of genes in the liver was analyzed using DNA microarrays. HFCD alone altered 471 genes (1.7%) versus CD. In CD-fed mice, RCl and RCh affected 170 (0.6%) and 321 (1.2%) genes, respectively. In HFCD-fed mice, RCl and RCh affected 109 (0.4%) and 223 (0.8%) genes. Opposite DE changes between HFCD and RC + HFCD occurred in immune recognition and fat-storage genes (Ccl24, Fabp7, Cd74, H2-Ab1, Srebf1, etc.). Uniform responses to HFCD and RC + CD were seen in Ppard, Irs-1, Tsku, Cyp26b1, Il1r1, Onecut1, Per1, Nlrd2, Rgs16, Grem2, Klf9, and Lpin1. RC effects were consistent with liver morphology. Key RC-targeted pathways included retinoid metabolism, PPAR signaling, and antigen presentation. In HFCD-fed mice, additional pathways were steroid biosynthesis, oxylipin metabolism, and Jak-STAT signaling. DBA/2J mice may exhibit an innate compensatory response involving PPAR signaling, Srebf1, and Socs2, and the contribution of polymorphisms in these genes merits separate investigation in future studies of obesity resistance. Full article

Clothianidin (CLO), a widely used neonicotinoid insecticide, may pose a health risk to waterfowl through contaminated feed ingredients and agricultural residues. This study investigated whether dietary Bacillus amyloliquefaciens (BA) could alleviate CLO-induced growth suppression and liver oxidative injury in goslings. Fourteen-day-old Holdobagy goslings were assigned to five treatments for 21 days: control, 2.5 mg/kg CLO, 2.5 mg/kg CLO plus 60 ppm BA, 10 mg/kg CLO, and 10 mg/kg CLO plus 60 ppm BA. CLO exposure reduced final body weight and average daily gain, increased liver index, elevated serum alkaline phosphatase (AKP), aspartate aminotransferase (AST), and malondialdehyde (MDA) levels, and decreased liver total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) activities (p < 0.05). Histological analysis further showed hepatocyte disorganization, vacuolar degeneration, congestion, and inflammatory infiltration, which were partially alleviated by BA supplementation. Serum untargeted metabolomics showed clear separation among treatment groups. CLO exposure altered 130 and 215 differential metabolites at the low and high doses, respectively, whereas BA supplementation regulated 115 and 170 differential metabolites under the corresponding CLO backgrounds (p < 0.05). These metabolites were mainly enriched in amino acid metabolism, ATP-binding cassette (ABC) transporters, purine metabolism, riboflavin metabolism, glutathione metabolism, glycerophospholipid metabolism, and fatty acid biosynthesis/degradation pathways. Liver transcriptomic analysis identified 761 and 1283 differentially expressed genes after low- and high-dose CLO exposure, respectively, while BA supplementation altered 338 and 440 genes (p < 0.05). Enriched pathways included peroxisome proliferator-activated receptor (PPAR) signaling, fatty acid metabolism, pyruvate metabolism, glycolysis/gluconeogenesis, pentose phosphate pathway, glutathione metabolism, cell adhesion molecules, and adipocytokine signaling. This study adds new evidence on the protective role of BA against CLO-induced toxicity in goslings by combining physiological, histological, metabolomic, and transcriptomic observations. Overall, BA partially mitigated CLO-induced growth inhibition and liver oxidative injury, potentially through coordinated regulation of redox homeostasis, lipid and energy metabolism, and liver metabolic remodeling. Full article

Mycobacterium tuberculosis (M. tb) possesses a unique, lipid-rich cell envelope that is critical for virulence, drug resistance, and persistence. Here, we identify the PPE family protein PPE57 as a key regulator of mycolic acid transport and host lipid exploitation. PPE57 physically interacts with the essential lipid transporter MmpL3, promoting trehalose monomycolate (TMM) translocation, enhancing trehalose dimycolate (TDM) synthesis, and increasing cell wall lipid content. Site-directed mutagenesis identified G175 as a critical residue for PPE57-MmpL3 binding. Deletion of PPE57 reduces cell wall thickness, alters lipid composition, and impairs biofilm formation. Mechanistically, PPE57 facilitates bacterial cholesterol acquisition, and during infection, activates the host PPAR-γ pathway in macrophages, leading to enhanced cholesterol uptake, lipid droplet accumulation, and increased intracellular triglyceride and cholesteryl ester levels. These changes provide a nutrient-rich niche that promotes bacterial survival and persistence. In a mouse model of infection, PPE57 deficiency results in reduced bacterial burden, milder lung pathology, and diminished lipid droplet-positive cell accumulation in lung tissues. These findings establish PPE57 as an essential accessory component of the MmpL3 lipid transport system, bridging mycobacterial cell wall assembly with host nutrient exploitation during persistent infection. Full article

Salinity is an important environmental factor affecting the physiological homeostasis of freshwater fish, yet the underlying mechanisms in grass carp (Ctenopharyngodon idella) gills remain unclear. Therefore, grass carp were exposed to different salinity levels for 60 days, and gill responses were evaluated using histopathological, ion regulatory, antioxidant, transcriptomic, and metabolomic analyses. Histological observations showed that high salinity (8 g/L) caused marked structural damage to the gill lamellae. Specifically, Na⁺ and Ca²⁺ concentrations and Na⁺/K⁺-ATPase activity significantly decreased, while K⁺ concentration and Ca²⁺-ATPase activity increased, revealing disrupted ion homeostasis. Salinity exposure also led to decreased antioxidant enzyme activities. Integrated omics analysis further demonstrated that a total of 2447 differentially expressed genes and 268 differentially expressed metabolites were identified, with significant enrichment in pathways related to biosynthesis of amino acids, arachidonic acid metabolism, glutathione metabolism, PPAR signaling, and calcium signaling. Notably, the PPAR and calcium signaling pathways showed positive enrichment under salinity stress, suggesting their potential involvement in the regulation of lipid metabolism, energy allocation, and cellular stress responses. Our findings indicated amino acid biosynthesis and arachidonic acid metabolism as key pathways involved in the adaptation of grass carp gills to salinity stress. Overall, chronic salinity exposure caused structural alterations, disrupted ion regulation, altered antioxidant status, and marked transcriptomic and metabolomic changes in grass carp gills, offering new insight into salinity adaptation in freshwater fish. Full article

Phytol, an acyclic diterpene alcohol and a key lipophilic side-chain moiety of chlorophyll, is widely distributed in nature. It exhibits potent antioxidant, anti-inflammatory, analgesic and broad-spectrum antibacterial activities. Notably, phytol can also effectively inhibit melanin production, repair the skin barrier, and exert profound anti-aging effects, making it a highly promising ingredient for daily skincare with substantial industrial application value. The skincare benefits of phytol are primarily achieved by constructing a multi-dimensional regulatory network involving defense, modulation and repair. Compared to conventional retinol-based skincare ingredients, phytol exhibits superior biocompatibility, mild irritation, and remarkable safety advantages. Nevertheless, its application is hindered by inherent limitations, including strong hydrophobicity, spontaneous aggregation tendency, and poor photothermal stability. These drawbacks severely restrict its dispersibility, storage stability and percutaneous bioavailability in aqueous cosmetic formulations. To address these deficiencies, nanodrug delivery systems (NDDS), such as liposomes, nanoemulsions, solid lipid nanoparticles and PLGA nanoparticles, have been widely employed. These nanocarriers can penetrate the skin barrier via the size effect, enabling targeted skin delivery and long-term controlled release of phytol. This review systematically summarizes the biological sources and metabolic fate of phytol, as well as its multi-mechanistic pharmacological effects on the skin. Furthermore, we outline the current application status and industrial development trends of phytol in mainstream cosmetics worldwide. This work aims to provide theoretical basis and forward-looking references for the development of high-efficiency, safe and stable phytol-derived skincare raw materials and topical formulations. Highlights: (1) Phytol, a natural acyclic diterpene alcohol, exerts multi-dimensional skincare effects including antioxidant, anti-inflammatory, whitening, anti-aging, and skin barrier repair activities via a defense–modulation–repair regulatory network. (2) Phytol may act as a mild, non-irritating functional alternative to retinoids, targeting PPAR/RXR pathways and avoiding TRPV1-mediated irritation, making it suitable for sensitive skin. (3) Poor water solubility and instability hinder phytol’s translation; nanodelivery systems effectively improve solubility, permeability, and sustained release. Full article

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation. Full article

Background: Chikungunya virus and dengue virus rank among the most clinically significant mosquito-borne pathogens worldwide, imposing substantial disease burdens in endemic regions. Despite their overlapping symptomatology, the diseases diverge markedly in prognosis. This disparity underscores the critical need for tools to differentiate these conditions and elucidate their distinct pathogenic mechanisms. Method: We conducted liquid chromatography–tandem mass spectrometry-based comparative metabolomic analyses to systematically compare plasma profiles from infected individuals. Results: We collected plasma samples from 26 chikungunya fever (CHIKF) patients, 49 dengue fever (DF) patients and 28 healthy individuals. Clinically, CHIKF patients exhibited a higher prevalence of rash (96.3% vs. 36.7%) and involvement of small joints, while DF patients showed prolonged fever and more severe hematological abnormalities. Metabolically, significant differences were observed in specific metabolites, such as eugenol sulfate, lysophosphatidylcholine (14:0/0:0), and piperine, which were dysregulated in both groups compared to healthy controls. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted unique metabolic perturbations in CHIKF, such as peroxisome proliferator-activated receptor (PPAR) signaling and mechanistic target of rapamycin complex (mTOR) pathways, suggesting potential mechanisms underlying CHIKV-induced arthritis. Conclusions: This study identifies distinct metabolic signatures and functional pathways associated with CHIKF and DF, offering a potential mechanism for differential diagnosis and therapeutic targets. The role of eugenol sulfate in modulating CHIKV-induced arthralgia is particularly promising, supported by its known anti-inflammatory properties. Full article

Though a number of Eimeria species have been described in geese, the host responses to these parasites at the molecular level have yet to be explored. In the present study, fresh fecal samples were collected for single-oocyst isolation. The recovered oocysts were identified based on molecular analysis using PCR and sequencing. Subsequently, we examined the transcriptional response of the Landes goose cecum following infection with the isolated Eimeria strain. Molecular analysis showed that the isolated Eimeria strain was Eimeria stigmosa, which was named the E. stigmosa SX-01 strain. Transcriptomic profiling identified 3806 differentially expressed genes (DEGs), including 2238 genes with increased expression and 1568 genes with decreased expression. The results obtained from the quantitative reverse transcription PCR (qRT-PCR) analysis confirmed that the RNA sequencing (RNA-seq) data were reliable. According to pathway enrichment analysis for the obtained DEGs, 24 pathways were significantly affected following infection with the E. stigmosa SX-01 strain, such as cytokine–cytokine receptor interaction, intestinal immune network for IgA production, cell adhesion molecules, gap junction, arachidonic acid metabolism, alpha-Linolenic acid metabolism, retinol metabolism, and PPAR signaling pathway. These transcriptional alterations were observed in E. stigmosa-infected geese without obvious clinical signs, indicating that E. stigmosa infection may trigger a strong subclinical host response related to metabolism, immune and inflammatory responses, and intercellular junctional complex-associated processes. Collectively, these findings have implications for better understanding the E. stigmosa–goose interactions at the molecular level and provide a foundation for future functional and comparative studies to dissect the pathogenic mechanisms and molecular markers associated with disease resistance, which are expected to inform the design of effective control strategies. Full article

Monascus yellow pigments, including monascin, ankaflavin, and the derivative monascinol, are azaphilone secondary metabolites produced by Monascus species. They have attracted attention as candidate functional-food ingredients because experimental studies indicate activity in pathways relevant to lipid and glucose metabolism. Available evidence, however, is heterogeneous and is derived predominantly from in vitro and animal studies; the human evidence is limited to small, short-term studies of Monascus-fermented preparations rather than isolated pigments. Reported associations with PPAR-α/γ and AMPK signaling, and with gut–liver-axis outcomes, should therefore be interpreted as mechanistic or preclinical observations. Monascus yellow pigments may offer a promising safety profile relative to monacolin K-containing preparations, but their long-term efficacy, dose standardization, and safety require confirmation in adequately powered human trials. Monascus-fermented products are being investigated beyond their traditional use as colorants and sources of monacolin K, partly because monacolin K has statin-like safety concerns. This review summarizes the structural diversity, biosynthetic pathways, and reported pharmacological activities of monascin, ankaflavin, and monascinol. Preclinical studies suggest that these azaphilones may influence PPAR-α/γ-, AMPK-, oxidative-stress-, and inflammation-related pathways and may affect lipid and glucose metabolism. Evidence for gut-microbiota modulation by monascinol is currently derived mainly from animal and mechanistic studies. Human data remain limited, including a small, short-duration trial of a Monascus-fermented preparation enriched in monascin and ankaflavin; these findings support short-term investigation but do not establish long-term clinical efficacy or comparative safety. Accordingly, Monascus yellow pigments should be regarded as promising candidate functional ingredients whose composition, bioavailability, dose, long-term safety, and clinical applicability require further rigorous evaluation. Full article

Abdominal fat deposition is an important economic trait in meat ducks, but the molecular mechanisms underlying individual variation in abdominal fat rate remain unclear. In this study, abdominal fat traits were measured in 316 male Pekin ducks, from which six ducks with high abdominal fat rates and six ducks with low abdominal fat rates were selected for transcriptomic and metabolomic analyses of abdominal adipose tissue. Considerable individual variation in abdominal fat rate was observed in the population, providing a phenotypic basis for divergent group selection. Transcriptomic analysis identified 549 differentially expressed genes, including 181 upregulated and 368 downregulated genes in the LF group relative to the HF group. Functional enrichment analysis revealed that these genes were mainly involved in lipid metabolism, fatty acid metabolism, glycerolipid and glycerophospholipid metabolism, triglyceride metabolism, cholesterol metabolism, lipid transport, and the PI3K-Akt signaling pathway. Among the representative candidate genes, FASN, AGPAT1, ELOVL4, PEMT, PLTP, LCAT, LIPA, and LIPG were upregulated, whereas FABP5 and FABP6 were downregulated in the HF group relative to the LF group. Metabolomic analysis detected 222 differential metabolic features. The putatively annotated metabolites among these features were mainly associated with cholesterol metabolism, primary and secondary bile acid biosynthesis, bile secretion, steroid biosynthesis, alpha-linolenic acid metabolism, PPAR signaling, and adipocytokine signaling pathways. Integrated transcriptomic and metabolomic analysis further highlighted potential gene–metabolite modules related to lipid synthesis/remodeling, cholesterol–bile acid metabolism, and lipid signaling. Overall, these findings provide an exploratory molecular framework for subsequent validation of abdominal fat deposition in Pekin ducks. The proposed candidate genes and putatively annotated metabolites require validation in independent duck populations and further functional studies. Full article

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases with limited therapeutic options. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of patients respond incompletely, and there is no effective therapy for PSC. Newer peroxisome proliferator-activated receptor (PPAR) agonists, e.g., seladelpar and elafibranor, received accelerated FDA approval as second-line treatments for PBC, and additional studies of PPAR agonists for PSC are underway. PPAR agonists have varying affinities for the PPAR isoforms (α, δ, γ), and the functional effects of isoform activation in humans are less known. Interindividual PPAR isoform expression varies across diseases and traditionally required invasive tissue biopsies for evaluation. Newer experimental approaches, such as extracellular vesicles (EVs) from liquid biopsies, can be used to characterize individual gene expression as an alternative (to tissue biopsy). The transcriptomic profiling of EVs uniquely allows for the quantification of coding and non-coding RNA transcripts, which may be used to study pathways relevant to PPAR expression and regulation and to identify biomarkers of treatment response to PPAR agonists in cholestasis. This review explores the application(s) of liquid biopsy-derived EVs for the identification of PPAR regulated pathways and its potential role in the treatment of PBC and PSC. Full article

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms—PPARα, PPARγ, and PPARβ/δ—that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ] and saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ] and bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively), demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with the placebo. Long-term open-label extension data from the ELATIVE trial have demonstrated sustained improvements in cholestatic biomarkers and stabilization of fibrosis markers over three years, with durable benefits on fatigue and pruritus. The ASSURE open-label study has confirmed the durability of seladelpar’s effects on biochemical response and pruritus through up to two years of treatment. Saroglitazar, a dual PPARα/γ agonist, has shown positive topline phase 3 results in the EPICS-III trial and received an FDA priority review designation. Bezafibrate has shown a survival benefit in large retrospective analyses and is used as a second-line therapy in Europe and Japan; notably, bezafibrate functions as a dual PPAR/pregnane X receptor (PXR) agonist, inducing CYP3A4 and efflux transporters that contribute to bile acid detoxification. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). PPAR agonists have also demonstrated therapeutic effects on liver fibrosis inhibition through direct modulation of hepatic stellate cell activation and suppression of fibrogenic signaling. This narrative review synthesizes the molecular pharmacology of PPAR isoforms; the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists; and their therapeutic applications across MASLD/MASH, alcohol-associated liver disease (ALD), PBC, primary sclerosing cholangitis (PSC), intestinal failure-associated liver disease (IFALD), and advanced chronic liver disease (ACLD). The evolution from single-isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy. Full article