Search Results (819)

Background/Objectives: The cerebral cortex is critical for neurological functions that are strongly affected by the aging process. Astrocytes play a central role in maintaining neurotransmitter balance and regulating antioxidant and anti-inflammatory responses, but these physiological functions may also decline with age. This study aimed to investigate the effects of melatonin, a molecule with known antioxidant, anti-inflammatory and neuroprotective properties, on astrocytes of mature cortical tissue obtained from adult Wistar rats. Methods: Primary cortical astrocyte cultures were obtained from neonatal and 90-day-old Wistar rats and treated with melatonin (300 µM for 24 h). We assessed cell viability and metabolism (MTT and extracellular lactate levels), glutamine synthetase (GS) activity, glutathione (GSH) content, release of cytokines, and the expression of genes and proteins associated with oxidative stress and inflammation by RT-qPCR and Western blotting. Results: Melatonin did not affect cell viability or lactate production. Moreover, there were no changes in GS activity, a key enzyme in glutamate metabolism, or in GSH levels, an antioxidant defense molecule synthesized by astrocytes. However, melatonin significantly reduced the expression of the nuclear factor NFκB, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS), while increasing interleukin 6 and 10 levels. Melatonin also upregulated the gene expression of the transcriptional factors Nrf2 and sirtuin 1 (SIRT1) and downregulated AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), while PGC-1α protein levels remained unchanged. A complementary analysis of astrocytes obtained from neonatal rats showed that melatonin did not change metabolic or redox parameters under basal conditions. Conclusions: Melatonin exerted anti-inflammatory effects on adult astrocyte cultures, likely through modulation of protective signaling pathways, such as Nrf2/SIRT1. These findings highlight the potential role of melatonin in preserving astrocytic function and mitigating age-related neuroinflammatory processes. Full article

Obesity is a chronic systemic disease characterised by insulin resistance, inflammation, and mitochondrial dysfunction. Hyperbaric oxygen therapy (HBOT), which involves the administration of 100% oxygen under elevated atmospheric pressure, has a well-established clinical application in the treatment of non-healing wounds and ischemia, and it is currently being investigated as an adjunctive therapy for obesity and metabolic disorders. The aim of this review is to provide a critical synthesis of recent (2012–2025) evidence regarding the mechanisms of HBOT action in the human body. Furthermore, it examines the metabolic effects and safety profile of HBOT in the context of obesity, with particular attention to experimental and preliminary clinical research. Preclinical studies have demonstrated that HBOT enhances insulin sensitivity, reduces adipose tissue inflammation, and modulates lipid metabolism. The proposed mechanisms include activation of Akt/AMPK signalling and GLUT4 translocation in skeletal muscle, resulting in improved glucose uptake and oxidation, as well as stimulation of thermogenesis in brown adipose tissue. In rodent models of obesity, HBOT has been shown to reduce adipose tissue mass, improve lipid profiles, and restore normal β-oxidation of fatty acids by normalising the expression of peroxisome proliferator-activated receptor-α and carnitine palmitoyl transferase 1B in muscle tissue. Preliminary clinical studies in humans indicate that HBOT enhances both systemic and tissue insulin sensitivity, accompanied by improved mitochondrial function and reduced endoplasmic reticulum stress. Despite these promising findings, data on the long-term efficacy, optimal treatment protocols, and safety of HBOT in obese individuals remain limited. In conclusion, HBOT appears to be a promising adjunctive approach in the management of obesity through the multidirectional improvement in metabolic functions. However, high-quality clinical trials are required to confirm its effectiveness, durability of outcomes, and safety profile across diverse patient populations. Full article

Background/Objectives: Changes in glucose metabolism impact central nervous system (CNS) homeostasis and, consequently, can lead to cognitive impairment and an increased risk for neurodegenerative and neuropsychiatric disorders. Astrocytes are glial cells that act as key regulators of brain glucose metabolism, thus representing important cellular targets for studies of different pathophysiological conditions, including hyperglycemia. Resveratrol, a natural polyphenol, has emerged as a potential protective strategy against diabetes and its complications; however, its glioprotective effects remain unclear. Based on these observations, we evaluated whether resveratrol could modify the inflammatory response in astroglial cells exposed to experimental hyperglycemic conditions. Methods: After reaching confluence, C6 astroglial cells were pre-incubated with 10 µM resveratrol in serum-free DMEM with 6 mM glucose for 24 h. The medium was then replaced with serum-free DMEM containing 12 mM glucose and 10 µM resveratrol for another 24 h. Controls were maintained in 6 mM glucose. Analyses included cell viability, metabolic activity, glucose and glutamate uptake, cytokine quantification by ELISA, and gene expression by RT-qPCR. Results: We show that high glucose levels modulate glucose and glutamate metabolism, and increase neuroinflammation, through the modulation of inflammatory mediators. In addition, high glucose upregulated the gene expressions of inducible nitric oxide synthase (iNOS), nuclear factor κB (NFκB), cyclooxygenase 2 (COX2), and Toll-like receptor 4 (TLR4) while decreasing mRNA levels of NLR family pyrin domain containing 3 (NLRP3) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). However, resveratrol was able to prevent most of these effects, particularly the high glucose-triggered inflammatory response. Resveratrol also modulated heme oxygenase 1 (HO-1) and nuclear factor erythroid-derived 2-like 2 (Nrf2), important targets associated with cellular protection. Conclusions: Our findings reinforce resveratrol as a potential glioprotective strategy against diabetes-related brain toxicity. Full article

Background/Objectives: Rosiglitazone (RSG), a potent PPARγ agonist for type 2 diabetes mellitus (T2DM), induces adverse adipogenic effects that limit clinical use. We investigated whether emodin (1,3,8-trihydroxy-6-methylanthraquinone, EMO), a natural anthraquinone, mitigates RSG-induced complications while enhancing its insulin-sensitizing benefits in severe obesity. Methods: Male ob/ob mice with established obesity and diabetes were treated for 4 weeks with RSG (10 mg kg⁻¹ day⁻¹), EMO (200 or 400 mg kg⁻¹ day⁻¹) or their combination. Metabolic profiling, organ function, and adipose histology were analyzed. RNA sequencing and mechanistic studies (Western blot, RT-qPCR, luciferase assays) in inguinal subcutaneous adipose tissue (iSAT), epididymal white adipose tissue (eWAT), and 3T3-L1 adipocytes were used to define EMO’s actions. Results: EMO co-treatment dose-dependently reduced RSG-induced weight gain, visceral adiposity (iSAT and eWAT mass, p < 0.05), and ectopic lipid deposition while ameliorating hepatorenal dysfunction. EMO synergistically enhanced RSG’s glucose-lowering effects. Mechanistically, EMO suppressed sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis (Srebp1, Acc, Fasn, Scd1; p < 0.05) and enhanced PPARγ-peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-driven thermogenesis via enhanced PPARγ transactivation and nuclear translocation. Thermogenic genes (Ucp1, Ppargc1a, Cidea; p < 0.05) were upregulated, with maximal uncoupling protein 1 (UCP1) induction in iSAT at 400 mg/kg EMO. Conclusions: EMO selectively enhances RSG’s glycemic benefits while attenuating its adipogenic effects in severe obesity by dual PPARγ modulation-inhibiting adipogenic pathways while amplifying thermogenesis. This strategy mitigates RSG’s adverse effects while improving insulin sensitivity, supporting the potential of EMO as a PPARγ adjunct therapy. Full article

Introduction/Objectives: Ginsenoside F1, a pharmacologically active saponin derived from Panax ginseng, exhibits diverse bioactivities, but its use is limited because it is difficult to purify and has high production costs. To overcome these challenges, a ginsenoside F1-enriched extract named SGB121 was developed. This study aimed to evaluate the therapeutic efficacy of SGB121 in a high-fat, high-carbohydrate (HFHC) diet-induced metabolic dysfunction-associated fatty liver disease (MAFLD) mouse model and to elucidate its mechanism of action using F1-based cellular assays. Methods: Male C57BL/6 mice (6 weeks old) were fed an HFHC diet to induce MAFLD and were treated with SGB121. Hepatic lipid accumulation, oxidative stress markers, and metabolic parameters were analyzed. In parallel, human hepatocellular carcinoma (HepG2) cells exposed to free fatty acids (FFAs) were used to assess oxidative stress and lipid accumulation. Mechanistic studies were conducted using purified F1 to examine adenosine monophosphate-activated protein kinase (AMPK) activation and related pathways. Results: SGB121 reduced hepatic lipid accumulation, malondialdehyde (MDA) levels, and fasting insulin while restoring glutathione (GSH) content and improving the homeostasis model assessment of insulin resistance (HOMA-IR) in MAFLD mice. In FFA-treated HepG2 cells, both SGB121 and F1 decreased reactive oxygen species (ROS), suppressed sterol regulatory element-binding protein 1 (SREBP1), enhanced peroxisome proliferator-activated receptor-α (PPARα) and β-oxidation, and restored insulin receptor substrate (IRS)/protein kinase B (Akt)/glucose transporter 2 (GLUT2) signaling. Conclusions: SGB121 ameliorates MAFLD and related metabolic dysfunction through antioxidant, lipid-regulating, and insulin-sensitizing actions, highlighting its potential as a safe multifunctional nutraceutical for MAFLD management. Full article

Alzheimer’s (AD) and Parkinson’s (PD) diseases are the most prevalent neurodegenerative disorders (NDs), posing a growing global health burden due to the lack of effective therapies. Current treatments offer only limited symptomatic relief without preventing the progression of NDs. In the search for novel therapeutic strategies, peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a promising therapeutic target because mounting evidence suggests that PPARα activation can effectively modify key pathological mechanisms related to NDs, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired transcriptional regulation, processes leading to protein misfolding and aggregation. This review focuses on the potential therapeutic relevance of PPARα activation in AD and PD, discussing mainly insights from preclinical studies. Indicatively, gemfibrozil (PPARα agonist) markedly reduced the beta-amyloid burden, microgliosis, and astrogliosis in the hippocampus of 5xFAD mice and ameliorated their spatial learning and memory. Fenofibrate (PPARα agonist) reduced the depressive-like behavior and memory deficits in rotenone-lesioned rats developing Parkinsonism. It also restricted the depletion of striatal dopamine and protected their substantia nigra pars compacta from dopaminergic neuronal death and α-synuclein aggregation. Clinical trials gave disparate results, indicating either a benefit of fenofibrate in cognitive decline of AD patients or limited efficacy. The role of PPARα agonists in PD is less well established in human trials, which provided limited evidence of neuroprotection and reduced neuroinflammation. Although current findings are promising, they underscore the necessity of further rigorous clinical validation of the efficacy of various PPARα agonists in the retardation or even prevention of AD and PD symptomatology in both genders and the development of reliable biomarkers for the early assessment of the impact of PPARα agonists on NDs. The safety of these drugs in the elderly and their longitudinal effectiveness should also be evaluated. Full article

Skin aging is primarily driven by oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. This study investigated the anti-senescence effects of fermented porcine placenta (FPP) and its dipeptides, leucine–glycine (LG) and proline–hydroxyproline (PH), in human epidermal keratinocytes (HEKs), using nicotinamide mononucleotide (NMN) as a reference for nicotinamide adenine dinucleotide (NAD⁺)-related pathways. FPP suppressed senescence-associated β-galactosidase (SA-β-gal) activity and Cyclin-dependent kinase inhibitor 2A (p16) expression while enhancing adenosine triphosphate (ATP) production and sirtuin 1 (SIRT1)–peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling. LG and PH exhibited distinct actions: LG improved redox balance by increasing the NAD⁺/NADH ratio and NAD(P)H quinone oxidoreductase 1 (NQO1) activity, whereas PH modulated cell cycle regulators and upregulated sirtuin 3 (SIRT3) expression. Although both peptides contributed to FPP’s effects, their combination did not fully replicate its overall activity, suggesting synergistic roles of multiple bioactive constituents. These findings highlight FPP as a multifactorial modulator of keratinocyte senescence, acting via mitochondrial and redox-related mechanisms. Full article

This study investigated the effects of vitamin E supplementation on growth performance, antioxidant capacity, and hepatic lipid metabolism in one-year-old juvenile Chinese sturgeon (Acipenser sinensis). A total of 270 fish (initial weight 1.37 ± 0.04 kg) were allocated into 9 fiberglass tanks and fed isonitrogenous and isolipidic diets with graded concentrations of vitamin E (DL-α-tocopherol acetate) including, 0, 1000, and 2000 mg/kg, respectively, for 2 months. Results showed that 1000 mg/kg vitamin E significantly improved growth performance and decreased hepatosomatic index. Dietary vitamin E supplementation significantly reduced the hepatic crude protein and crude lipid levels, withnot significantly affecting moisture and crude ash. Dietary vitamin E led to significant increases in plasma high-density lipoprotein cholesterol and vitamin E levels, while decreasing plasma low-density lipoprotein cholesterol. Additionally, it raised liver vitamin E content and reduced hepatic triglycerides, total cholesterol, crude protein, and crude lipid levels. Vitamin E also significantly downregulated mRNA levels of lipogenesis-related genes (ACC1, acetyl-CoA carboxylase 1; FASN, fatty acid synthase; and PPARγ, peroxisome proliferator activated receptor γ) and inhibited the enzyme activities of ACC1 and FASN, while upregulating lipolysis-related genes (HSL, hormone-sensitive lipase; CPT1, carnitine palmitoyltransferase 1α, and PPARα, peroxisome proliferator activated receptor α) and enhancing the activities of HSL and CPT1α. Furthermore, vitamin E supplementation significantly improved plasma reduced glutathione and superoxide dismutase activities, lowered plasma reactive oxygen species, malondialdehyde levels, and hepatic malondialdehyde contents, and upregulated mRNA levels of hepatic Nrf2 (nuclear factor-erythroid 2 related factor 2), Keap1 (Kelch-like epichlorohydrin associating protein 1), and CuZnSOD (copper/zinc superoxide dismutase). In conclusion, dietary 1000 mg/kg vitamin E supplementation could improve growth performance, enhance antioxidant capacity, and reduce liver fat deposition, indicating its potential as a beneficial dietary additive for promoting health and lipid regulation in juvenile Chinese sturgeon. Full article

Central lipid metabolism disorders are crucial for the development of Alzheimer’s disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ’s strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression. Full article

To enhance the nutritional value of sheep fat, high-melting-point solid fat (HSO) and low-melting-point liquid oil (LSO) were prepared from Altay sheep rump fat via solvent fractionation. The effects of HSO and LSO on lipid metabolism and intestinal health were evaluated in a mouse model. Results showed that HSO, rich in saturated fatty acids (SFA), induced obesity, dyslipidemia, and colonic inflammation in mice. These adverse effects were associated with the upregulation of hepatic lipid synthesis genes such as Sterol regulatory element-binding protein 1c (SREBP-1c) and Fatty acid synthase (FAS), as well as increased expression of pro-inflammatory cytokines including Tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) in the colon. In contrast, LSO, which was predominantly composed of unsaturated fatty acids (UFA), did not cause significant metabolic disorders. Instead, it promoted the upregulation of fatty acid oxidation-related genes such as Peroxisome proliferator-activated receptor alpha (PPARα) and Acyl-CoA oxidase 1 (Acox1), helped maintain intestinal microbial balance, and enhanced the production of beneficial short-chain fatty acids (SCFAs), particularly butyrate and propionate. In conclusion, solvent fractionation effectively modulates the fatty acid composition of sheep fat, thereby influencing lipid metabolism and inflammatory responses through the regulation of key gene expression and modulation of the gut microenvironment. Full article

Background and Objectives: Heterotopic ossification (HO) involves abnormal bone growth in soft tissues. Current treatments are ineffective and prone to adverse effects, suggesting the need for new HO therapies. Intramembranous bone growth is led by osteoblasts. Since osteoblastogenesis and adipogenesis are opposed and mutually controlled processes, this study aims to identify a new repurposed therapeutic tool to inhibit osteoblastogenesis through adipogenesis promotion. Methods: We performed docking experiments between peroxisome proliferator-activated receptor-γ and bone metabolism-affecting drugs, namely, thiazolidinediones (rosiglitazone, pioglitazone), indomethacin, and dexamethasone, to test tritherapy antiosteoblastogenic effect. Mouse mesenchymal stem cells (C3H10T1/2), human osteoblast-like cells (SaOS2 and primary preosteoblasts), and mouse chondrocytes (ATDC5) were differentiated in the presence of these compounds. The effects on osteoblastogenesis, adipogenesis, and endochondral ossification were analysed through marker gene expression via RT–qPCR. Additionally, primary human HO cells and a congenital HO patient were treated with the selected drug combination (P-tritherapy). Results: Tritherapy significantly and synergistically promoted the expression of an adipogenic marker (fatty acid-binding protein 4) and decreased the expression of an osteoblastogenic marker (osteopontin). In an endochondral ossification model, it reduced ossification markers (collagen-2α1) expression, and in HO cells, it increased adipogenesis markers’ expression. Clinically, P-tritherapy administration prompted bone resorption in a patient with progressive osseous heteroplasia. Conclusions: Tritherapy induced adipogenesis while inhibiting osteoblastogenesis and endochondral ossification, demonstrating its potential as a new therapeutic tool to prevent abnormal bone growth. These results were consistent with bone turnover modification observed in a congenital HO patient. This concordance underscores tritherapy potential for rapid and safe translation to prevent HO. Full article

The peroxisome proliferator-activated receptors (PPAR-α, PPAR-δ, and PPAR-γ) are transcription factors that belong to the nuclear hormone receptor superfamily. Upon activation by specific lipids, they regulate gene expression by directly binding to PPAR response elements (PPREs) in the DNA. Although the functions of the different PPARs are specific to the isoform, tissue, and context, all three PPARs are generally involved in energy homeostasis through lipid sensing in physiological conditions. Importantly, there is increasing evidence linking PPARs with malignant behavior in cancer, regulating features frequently attributed to the aggressive subpopulation of cancer stem cells (CSCs): self-renewal, tumor initiation, chemoresistance, metastasis, and immune evasion. However, contradictory effects have been described for each isoform in various cancer types, and their implication in these malignant features may not consistently follow a pro- or anti-tumoral pattern. In this review, we revise the current knowledge on the role of the PPAR family members in cancer, with a special focus on cancer stemness, and discuss the potential for PPARs as therapeutic targets in CSC-driven relapse and resistance. Full article

The aim of the present study is to evaluate the impact of chromium (Cr) supplementation on glucose and lipid metabolism in breast muscle in broilers under heat stress. A total of 220 day-old broiler chicks were reared in cages. At 29 days old, 180 birds were randomly assigned to three treatments (0, 400, and 800 µg Cr/kg, as chromium picolinate) and transferred to climate chambers (31 ± 1 °C, 60 ± 7% humidity) for 14 days. Growth performance, carcass traits, serum biochemical indices, fasting glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), as well as muscle metabolomic profiles and gene expression related to energy and lipid metabolism were analyzed. The results showed that, compared with the heat stress group, the groups supplemented with 400 and 800 µg Cr/kg showed higher dry matter intake and average daily gain, breast muscle ratio, and lower feed conversion ratio and abdominal fat ratio; chickens supplemented with 400 and 800 µg Cr/kg showed significantly lower serum corticosterone (CORT), free fatty acids, and cholesterol levels compared with the heat stress (HS) group (p < 0.05). Fasting blood glucose and HOMA-IR were also significantly reduced, while fasting insulin was significantly increased in the Cr-supplemented groups (p < 0.05). Metabolomic analysis revealed that Cr supplementation regulated lipid and amino acid metabolism by altering key metabolites such as citric acid, L-glutamine, and L-proline, and modulating pathways including alanine, aspartate, and glutamate metabolism, and glycerophospholipid metabolism. Furthermore, Cr supplementation significantly upregulated the expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 α (PGC-1α), ATP Binding Cassette Subfamily A Member 1 (ABCA1), Peroxisome Proliferator-Activated Receptor α (PPARα), and ATP Binding Cassette Subfamily G Member 1 (ABCG1) in both the hepatic and muscle tissue. This paper suggested that chromium supplementation may enhance energy metabolism and lipid transport like the findings of our study suggested. Full article

To assess the influence of dietary bile acid (BA) on the phenotype associated with hepatic lipid metabolism and its regulation of lipid homeostasis in gibel carp (Carassius auratus gibelio) under high-fat diet (HFD) conditions, five HFDs were designed using soybean oil (SO) as the single lipid source and supplemented with 0, 200, 400, 600, and 800 mg/kg BA (designated as BA0, BA200, BA400, BA600, and BA800, respectively). Juvenile fish (32.37 ± 0.13 g) were fed five BA-added HFDs (12% SO) for 8 weeks. Considerably lower levels of aspartate transaminase, alanine aminotransferase, low-density lipoprotein, triglyceride, and total cholesterol in the serum were observed in gibel carp fed with HFDs with 400–600 mg/kg BA (p < 0.05). The hepatocytes of the BA400 and BA600 groups were intact without abnormal architecture or histopathological changes, compared to other groups. The presence of most genes related to fatty acid biosynthesis decreased significantly with the addition of 400–600 mg/kg BA (p < 0.05), while the gene expressions of hormone-sensitive lipase, adiponectin receptor 2, and peroxisome proliferator-activated receptor α were variably up-regulated, along with the elevation of dietary BA (p < 0.05). Critical genes involved in bile acid and cholesterol synthesis were obviously down-regulated in gibel carp receiving 600–800 mg/kg dietary BA (p < 0.05), despite the sterol 27-hydroxylase (cyp27a1) gene in the BA800 group (p < 0.05). Moreover, hepatopancreas from the BA0 and BA600 groups were isolated for transcriptome sequencing, identifying 7040 differentially expressed genes (DEGs). The enriched KEGG pathways of DEGs mainly included steroid biosynthesis, protein digestion and absorption, etc. Seven randomly selected DEGs were validated using qRT-PCR and were in agreement with the RNA-seq results. Consequently, the appropriate supplementation of dietary BA for juvenile gibel carp is recommended at doses of 400–600 mg/kg in SO-based HFDs, which could contribute to the amelioration of HFD-induced excessive fat deposition in the hepatopancreas of gibel carp by both inhibiting fatty acid intake, biosynthesis, and steroid production and enhancing lipid decomposition. The findings may elucidate the physiological role of exogenous BA in fish and its underlying mechanism, providing references for the reasonable application of BA in aquafeeds and the prevention of HFD-induced metabolic dysfunction in fish. Full article

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by cholestasis and progressive fibrosis. While ursodeoxycholic acid (UDCA) remains the first-line therapy, approximately 30–40% of patients have an inadequate biochemical response, increasing the risk of disease progression. Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was the first second-line agent approved by the only Food and Drug Administration (FDA) and has demonstrated moderate biochemical efficacy but limited tolerability due to dose-dependent pruritus and safety concerns in cirrhosis. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, showed substantial alkaline phosphatase (ALP) reductions when added to UDCA, although its long-term benefit remains unconfirmed in large-scale trials and its use remains off-label in the United States, unlike FDA-approved agents. Seladelpar, a selective peroxisome proliferator-activated receptor delta (PPAR-δ) agonist, and elafibranor, a dual PPAR-α/δ agonist, have both recently received FDA accelerated approval after demonstrating significant improvements in ALP, biochemical response rates, and pruritus relief in phase 3 trials. This review summarizes these second-line therapies’ mechanisms, efficacy, safety, and limitations emphasizing the need for individualized treatment decisions and ongoing research into long-term clinical outcomes. Full article