Search Results (1,003)

Pleomorphism in cells encompasses a variety of morphological features, such as heterogeneity in the size and shape of cells and nuclei, irregularity of the nuclear membrane, hyperchromasia, and peculiarities of cell organelles. Pleomorphism in mammalian cells is associated with genetically unstable neoplasms and is frequently accompanied by high rates of proliferation and low differentiation status. Among soft tissue sarcomas, a group of tumors characterized by the pleomorphic phenotype can be distinguished. Pleomorphic soft tissue sarcomas are a rare, understudied group of soft tissue sarcomas with aggressive behavior, low survival rates, and high resistance to standard chemotherapy treatment. Knowledge of the mechanisms behind the pleomorphic features, common genetic and epigenetic alterations, and their association with aggressive tumorigenesis is essential for advancing patient care for this group of sarcomas. In this narrative review, we consolidate existing evidence concerning clinical features of pleomorphic sarcomas, their possible histogenesis, the common drivers and transcriptional networks, and the potentially available approaches for treatment. Full article

Despite recording Indonesia’s highest provincial economic growth rate at 39.10 percent in 2025, Sofifi, the designated capital city of North Maluku Province, continues to exhibit comparatively low urban vitality more than fifteen years after its formal inauguration. This trend raises important questions about the conditions under which capital-city relocation fosters intensity, diversity, and continuity of economic activities in the new city. Drawing on a mixed-methods case study approach integrating geographic information system (GIS)-based spatial analysis, qualitative examination of governance arrangements, and comparative analysis of non-autonomous provincial capitals in Indonesia, this paper assesses urban vitality in Sofifi across three dimensions: socio-economic indicators, infrastructure provision and accessibility, and institutional and land-related constraints. The findings reveal a persistent gap between Sofifi’s administrative status and its urban functionality, primarily explained by institutional lock-in rooted in its non-autonomous city status, a national moratorium on regional proliferation, and unresolved jurisdictional conflicts. The paper concludes that formal assignment of capital city status does not confer urban vitality. The evidence from Sofifi suggests that when the designated capital lacks the institutional prerequisites, including autonomous urban governance, it is nothing more than an administrative outpost: a place where government is formally located but where the conditions for urban life are structurally constrained. Full article

The gastrointestinal tract is a critical target of acute radiation exposure. Severe radiation exposure can deplete epithelial stem and progenitor cells, compromise barrier integrity, alter host–microbe interactions, and drive fluid loss, inflammation, and systemic decline. Mammalian models remain essential for clinical translation, but their cost and complexity constrain sample sizes, statistical power, large-scale mechanistic discovery, and countermeasure screening. The adult Drosophila melanogaster midgut provides a complementary in vivo platform containing intestinal stem cells, absorptive enterocytes, enteroendocrine cells, epithelial junctions, an associated microbiota, and conserved innate immune and injury-response pathways. Direct irradiation studies have demonstrated DNA damage, altered stem cell proliferation and differentiation, epithelial plasticity, apoptosis, autophagy-associated responses, morphological disruption, barrier failure, microbiome changes, and reduced survival. These phenotypes can be modulated by genotype, sex, diet, microbial status, antioxidant capacity, and regenerative signaling. This review evaluates the biological rationale, direct evidence, experimental assays, and countermeasure applications supporting the fly midgut as a model for studying gastrointestinal radiation injury. Although Drosophila has a long history of use in radiation research, our analysis indicates that the fly midgut is best positioned not as a miniature model of clinical gastrointestinal acute radiation syndrome, but as a genetically precise and scalable system for identifying conserved mechanisms and prioritizing interventions for validation in mammalian models. Full article

Peutz–Jeghers syndrome (PJS) presents an apparent biological paradox: heterozygous germline pathogenic variants in STK11 predispose to predominantly benign hamartomatous growth while conferring a markedly elevated lifetime risk of cancer, whereas somatic STK11 inactivation in established tumors is frequently associated with aggressive progression and therapeutic resistance. STK11 encodes liver kinase B1 (LKB1), a serine/threonine kinase that integrates metabolic, oxidative, architectural, and immune stress responses. Rather than acting solely as a direct brake on proliferation, LKB1 couples cellular growth, survival, and tissue organization to environmental fitness. We therefore propose a context-dependent stress adaptation framework in which impairment of STK11/LKB1 signaling relaxes stress-imposed constraints on cellular fitness, while the ultimate biological outcome is determined by allelic status, tissue context, and cooperating genetic alterations. In PJS, a heterozygous germline STK11 pathogenic variant creates a constitutional cancer predisposed state in which one functional allele is initially retained, although subsequent loss or impairment of the remaining allele may occur during tumor evolution. In sporadic cancers, somatic STK11 inactivation is often biallelic and frequently cooperates with alterations in KRAS, KEAP1, TP53, NF1, or PI3K-pathway genes. These genetic contexts can promote metabolic reprogramming, redox adaptation, autophagy dependence, immune exclusion, cellular plasticity, and therapeutic resistance, with the strongest mechanistic and clinical evidence currently derived from lung adenocarcinoma (LUAD). Within this framework, enhanced persistence under metabolic, oxidative, immune, and therapy-induced stress does not exclude proliferative effects of STK11 loss but provides a permissive background upon which cooperating oncogenic programs can drive clonal expansion and malignant progression. Stress adaptation creates dependencies on interconnected buffering systems, including antioxidant defenses, autophagy, metabolic plasticity, and ferroptosis suppression. Therapeutic strategies that simultaneously disrupt multiple compensatory pathways may therefore exceed tumor adaptive capacity, convert stress tolerance into therapeutic vulnerability, and provide a rational framework for treating LKB1-deficient tumors and other stress-adapted cancers. Full article

Background/Objectives: Colon adenocarcinoma is a heterogeneous disease, and tumours of similar pathological stage may differ in their metabolic and proliferative characteristics. Stearoyl-CoA desaturase (SCD) is involved in lipid metabolic reprogramming and may reflect aspects of tumour biology. The main goal of this study was to analyse SCD expression and its associations with clinicopathological factors, particularly focusing on histological grade. The relationship between SCD and proliferating cell nuclear antigen (PCNA) was evaluated as a secondary objective. Methods: Public TCGA/UALCAN and CPTAC/UALCAN data were examined as supportive transcriptomic and proteomic observations. Immunohistochemical SCD and PCNA expression was assessed in 113 patients with colon adenocarcinoma, and SCD localisation was additionally examined by qualitative immunogold electron microscopy. Standardised SCD and PCNA scores were combined with equal weighting to generate a secondary exploratory z-score. Associations with clinicopathological characteristics were assessed using appropriate univariable analyses, while the relationship between SCD and PCNA and the potential incremental contribution of SCD beyond PCNA were examined using correlation and exploratory regression-based analyses. ROC analyses were used only as exploratory descriptions of statistical separation between predefined clinicopathological groups. Results: Observations from supportive public databases indicated that SCD expression was higher in tumour tissue compared to normal tissue at both the transcriptomic and proteomic levels. In the institutional cohort, SCD expression was elevated in tumour tissue relative to matched non-neoplastic mucosa and was associated primarily with histological grade but not with nodal status or pathological stage. SCD showed a modest positive correlation with PCNA. The secondary exploratory combined SCD–PCNA score was associated with histological grade and with nodal status but did not outperform PCNA alone. Adding SCD to PCNA provided only limited incremental information for G3 histology and no incremental value for nodal involvement. Conclusions: SCD is a tumour-associated metabolic marker in colon adenocarcinoma, with its strongest association observed for histological grade. The combined score should not be interpreted as a biological entity or superior biomarker. Full article

The Northwest Xizang White Cashmere goat has a high global reputation for good goat cashmere germplasm characteristics, and its cashmere industry is the economic pillar of the herdsmen in the northwest plateau of Xizang. Cashmere is produced by the secondary hair follicles of the skin, and the key period of hair follicle development is from birth to 3 months old. This study aimed to explore how early compound nutritional intervention affects lamb growth performance and secondary hair follicle development. We assessed skin follicle density and performed skin transcriptomic and multi-omics analyses to clarify this regulatory effect. The trial was performed at the Northwest Xizang White Cashmere Goat Breeding Farm, Ritu County, Ngari region, Xizang. Thirty newborn single lambs of comparable birth status were randomly divided into control and early compound nutritional intervention groups (n = 15 per group). The results showed that early compound nutritional intervention significantly increased the secondary hair follicle density, total hair follicle density, and secondary/primary hair follicle (S/P) value of lambs (p < 0.05). However, there was no significant difference in the average cashmere fineness between the two groups (p > 0.05). The transcriptome, proteome, and metabolomics analyses of the skin revealed candidate genes related to hair follicle development and the regulation of cashmere fineness: keratin structural genes (KRT10, KRT18, KRT26), cell proliferation and adhesion-related regulatory genes (ITGB2, CSF1R, AKT1), and extracellular matrix coding genes (COL6A1, COL6A2, COL6A6). Moreover, the results revealed that key proteins related to hair follicle development include RBP4, KAP13-3, KRTAP3-1, KRTAP27-1, DKK3, ITGB2, and DUSP23. The differentially expressed metabolites, 15-Deoxy-delta12,14-Prostaglandin J2 and Thromboxane B2 (TXB2), modulate prostaglandin-associated pathways; altered pathway activity subsequently regulates the expression of hair follicle functional genes and key proteins, which may in turn indirectly regulate hair follicle growth and development, thereby affecting hair follicle density and, by extension, cashmere production performance. Therefore, early compound nutritional intervention of Northwest Xizang White Cashmere goats promotes the growth and development of secondary hair follicles. The identified candidate genes and key proteins involved in secondary hair follicle development provide a reference for exploring the mechanism of hair follicle development. Full article

In pigs, the establishment of pregnancy depends on tightly coordinated molecular interactions between the conceptus and the maternal endometrium during the peri-implantation period. Adipokines, peptide hormones produced by adipose tissue, function as endocrine mediators linking metabolic status with uterine function. Omentin-1, a hormone belonging to the adipokines group, is hypothesized to play a potential role in regulating female reproductive functions through its influence on uterine functions. Therefore, this study investigated the effects of omentin-1 on endometrial progesterone and oestradiol secretion using radioimmunoassay, on the abundance of key steroidogenic proteins and Akt phosphorylation using Western blot, and on endometrial cell proliferation and apoptosis using flow cytometry. Results showed that its actions are characterised by promotion of progesterone-dominant conditions, selective modulation of steroidogenic pathways, activation of Akt signalling, and cell-type-specific regulation of proliferation and apoptosis. This combination of effects positions omentin-1 as a previously unrecognised regulator of endometrial adaptation and suggests that adipokines may represent an important mechanistic link between metabolic status and reproductive success. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article

Chlorogenic acid (CGA) exhibits anticancer activity in colorectal cancer (CRC), but its clinical application is limited by low lipophilicity. To improve its physicochemical properties, four CGA esters (methyl, ethyl, n-propyl, and n-butyl chlorogenates) were synthesized and evaluated. Physicochemical properties were characterized in silico, and their biological activity was assessed in SW480, HT-29, and non-tumoral NCM460 cell lines using viability assays and flow cytometry. Molecular docking studies were performed to investigate the interactions of CGA and its esters with proteins involved in cell-proliferation-related signaling pathways. In silico analysis showed a progressive increase in LogP values across ester derivatives. All esters complied with Lipinski’s rule of five, whereas none met Veber’s rule due to their predicted topological polar surface area (TPSA) values. The esters induced dose- and time-dependent reductions in cell viability, with n-butyl chlorogenate exhibiting the strongest cytotoxic activity and a significantly lower IC₅₀ value within the tested concentration range. This derivative showed preferential cytotoxic activity toward SW480 cells while exhibiting only limited effects in non-tumoral NCM460 cells. In addition, n-butyl chlorogenate induced changes in mitochondrial oxidative status and phosphatidylserine externalization, consistent with apoptosis-associated cellular changes. Overall, these findings demonstrate that esterification modifies the physicochemical profile of CGA ester derivatives and is associated with enhanced cytotoxic activity. Increased lipophilicity was associated with enhanced cytotoxic activity, supporting further optimization of these compounds for CRC research. Full article

Kidney cystic epithelium primarily comprises proliferating A-intercalated (A-IC) cells in humans and mouse models of TSC. These studies explored the expression of transcription factors (TF) that drive the development of A-IC cells and the downregulation of B-intercalated (B-IC) cells, as well as the status and localization of Tsc1 and Tsc2 in epithelial cells lining the cysts. Transcriptome studies indicated enhanced expression of the following TFs: DMRT2, FOXI1, and FOXP1 in young TSC mice, and DMRT2 and FOXI1 in aged mice. The expression of Hmx2 decreased in TSC mice of all ages. Our studies further demonstrated: (1) distinct and predominant DMRT2 and FOXP1 localization in the cystic epithelium of in TSC mouse models; and (2) expression of Foxi1, Tsc1, and Tsc2 in epithelial cells lining the kidney cysts. Expression of DMRT2, FOXI1, and FOXP1 is enhanced in the A-IC cells lining the kidney cysts of TSC mouse models. In the same models, the expression of Hmx2 mRNA is decreased and is accompanied by the loss of B-IC cells in cyst epithelia. Both DMRT2 and FOXP1 localized to the nucleus of A-IC cells of the renal cysts, suggesting that TSC kidney cystogenesis is driven by factors that exclusively promote A-IC expansion. Full article

This study evaluated the effects of dietary LC inclusion (0, 50, 100, 200, and 400 mg/kg) in Pekin ducklings from 7 to 65 days of age on growth performance, carcass traits, metabolic profile, immune status, and economic efficiency. A total of 250 unsexed 7-day-old Pekin ducklings were randomly allocated to five dietary treatment groups, each comprising five replicates of 10 ducklings. The linear response plateau analysis estimated LC breakpoints of approximately 50 mg/kg diet for body weight gain and feed conversion ratio. Additionally, LC significantly improved carcass yield and crude protein content of the meat, as well as enhanced its antioxidant capacity. Physiologically, LC enhanced hematological indices, lipid metabolism, and thyroid hormone activity, without adversely affecting liver function. Moreover, LC favorably modulated the intestinal microbiota by increasing the abundance of beneficial Lactobacillus spp. and reducing pathogenic bacteria. Furthermore, it improved immune status, as indicated by higher immunoglobulin levels, lysozyme and phagocytic activities, and lymphocyte proliferation. LC significantly enhanced the mentioned parameters without inducing any adverse effects; however, the magnitude of the response plateaued and subsequently declined at higher inclusion levels (200–400 mg/kg). The improvements in performance and health status were attributed to the enhanced fatty acid oxidation, energy metabolism, antioxidant defense, and immunomodulatory effects of LC. In conclusion, including 50 mg L-carnitine/kg in the diet represents an effective and appropriate nutritional strategy under the conditions of the present study to optimize growth performance, carcass quality, nutrient digestibility, health status, and economic profitability in Pekin duck production systems. Full article

Background/Objectives: Metastatic colorectal cancer (mCRC) remains difficult to treat, largely due to chemotherapy resistance. Mutations in TP53 impair apoptosis and are associated with poor response to irinotecan. This study aimed to determine whether targeting Survivin, a key inhibitor of apoptosis, and using the disulfiram-derived compound CuET could restore apoptotic signaling and improve irinotecan efficacy. Methods: Human CRC cell lines with varying TP53 status and murine tumor models were treated with irinotecan (or its active metabolite SN-38), the Survivin inhibitor YM-155, and CuET, alone or in combination. Cell viability, clonogenic survival, and apoptotic signaling were assessed using cytotoxicity assays, flow cytometry, confocal microscopy, and Western blotting. In vivo efficacy was evaluated in xenograft and syngeneic mouse models through tumor growth measurements and histological analyses. Results: Inhibition of Survivin with YM-155 enhanced irinotecan-induced cytotoxicity and promoted caspase-dependent apoptosis in CRC cells. Irinotecan treatment induced Survivin expression, suggesting an adaptive resistance mechanism that was reversed by YM-155. CuET demonstrated potent cytotoxic activity independent of TP53 status and partially suppressed Survivin expression. Importantly, CuET restored sensitivity to irinotecan in TP53-deficient models and significantly enhanced antitumor efficacy in vivo, leading to reduced tumor growth, decreased proliferation, and increased apoptosis. Conclusions: These findings identify Survivin-mediated apoptotic resistance as a key determinant of irinotecan response in CRC. Targeting this pathway, either directly through Survivin inhibition or through CuET-induced stress responses, restores apoptotic sensitivity and enhances chemotherapy efficacy. This study supports the development of combination strategies incorporating CuET to overcome resistance in TP53-mutant CRC. Full article

Cardiovascular disease causes the largest number of deaths across the world. The weak regenerative ability of adult hearts originates from limited cell proliferation and polyploidization of postnatal cardiomyocytes, which severely hinders tissue repair after myocardial injury. Fetal development represents a critical window during which maternal physiological and metabolic status can shape long-term offspring cardiac structure and function. Maternal exercise represents a safe nonpharmacological prenatal intervention that confers long-term benefits to offspring health. Available evidence indicates that maternal exercise enhances placental apelin secretion and elevates α-ketoglutarate (α-KG) levels in fetal brown adipose tissue, liver, and skeletal muscle. The apelin and α-KG signaling cascade participates in epigenetic regulation and confers protective effects on offspring metabolic health. Independent animal experiments have further validated that supplementation with either apelin or α-KG alleviates myocardial infarction (MI)-induced cardiac injury in adult mice, with α-KG showing direct evidence of reactivating cardiomyocyte proliferation. Nevertheless, it remains poorly elucidated whether maternal exercise could modulate fetal cardiomyocyte proliferative capacity in offspring through apelin- or α-KG-associated signaling. This narrative review integrates current evidence and proposes a testable framework in which maternal exercise influences fetal cardiac growth and regenerative potential through placental, metabolic, and epigenetic signaling. Because direct evidence remains limited, this model should be regarded as a hypothesis that requires further experimental validation. Full article

Background/Objectives: Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Conventional computed tomography (CT) is the preferred imaging modality for evaluating pulmonary nodules because of its high spatial resolution; however, it primarily provides morphological information, including lesion size, shape, and density. Dual-energy CT (DECT), a more recent imaging technique, uses two different energy levels to enable material decomposition and quantitative parameter assessment. These parameters may provide additional information regarding tumor perfusion, vascularization, and tissue composition. This rapid review aimed to evaluate the current evidence regarding the clinical utility of DECT in the detection, characterization, and staging of lung tumors. Methods: This rapid review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed in the PubMed and Cochrane Library databases for studies published between 2005 and 2026. Studies were included if they evaluated the detection, characterization, or staging of lung tumors using quantitative DECT parameters. Case reports, editorials, duplicate studies, and studies without quantitative DECT data were excluded. Descriptive data analysis was performed using Microsoft Excel. Results: A total of 24 studies were included, comprising 18 retrospective (75%) and 6 prospective studies (25%). Only one study evaluated the role of DECT in lung tumor detection, demonstrating improved detection of mixed ground-glass nodules and invasive adenocarcinoma. Significant correlations were found between iodine uptake and tumor perfusion, highlighting the potential of DECT to improve differentiation between benign and malignant lesions. Several studies also demonstrated associations between DECT parameters and tumor biomarkers, including Ki-67 Proliferation Index (Ki-67) expression, Epidermal Growth Factor Receptor (EGFR) mutation status, Programmed Death-Ligand 1 (PD-L1) expression, and treatment response in non-small cell lung cancer. In addition, DECT provided complementary metabolic information regarding tumor malignancy and showed correlations between iodine uptake and fluorodeoxyglucose (FDG) parameters. Associations between iodine volume and tumor differentiation grade were also reported. One study demonstrated the potential role of DECT in tumor staging by predicting mediastinal lymph node metastasis. Across all included studies, iodine-based parameters (50%), radiomics and material decomposition parameters (16.67% each), and spectral attenuation parameters (12.50%) were the most frequently investigated DECT metrics. Conclusions: DECT appears to be a promising complementary imaging technique that provides quantitative perfusion-related and compositional surrogate information beyond the morphological assessment offered by conventional CT. However, the current evidence remains heterogeneous and is largely based on retrospective studies with relatively small patient cohorts. Larger prospective studies with standardized imaging protocols are necessary to further establish the clinical utility of DECT in lung tumors. 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