PPARA (Peroxisome Proliferator Activated Receptor Alpha)

Collectively, the 'dual‑role' behavior of HECT‑type E3 ligases is governed by disease‑specific contexts, substrate selection, ubiquitin linkage type (K48 vs. K63), and integration of microenvironmental cues. Although this functional duality presents significant translational challenges, understanding these dual regulatory networks provides critical insights into the pathogenesis of liver diseases and reveals potential avenues for targeted interventions.

Furthermore, we identify FGF2 as a synaptic effector of this pathway and highlight PPARα (peroxisome proliferator-activated receptor alpha) as a putative therapeutic target. These results establish astrocyte fatty acid metabolism as a critical mechanistic contributor to MDD and a promising avenue for treatment.

Specifically, both BTMAC and DAD were associated with prolonged QRS time, whereas C8-DDAC was related to increased QT interval, QTc interval, and RV5/SV1 amplitude, as well as a reduced QRS time...Taken together, this study provides the first population-based evidence of QAC-associated cardiotoxicity and proposes the underlying biomolecular alternations. These insights offer a scientific foundation for developing targeted strategies to prevent and mitigate environmentally induced cardiovascular risks in susceptible populations.

Clinically, reduced SIRT6 expression coupled with elevated NCOA2 and mitochondrial/β-oxidation markers correlates with metastatic progression in bladder cancer. Together, these findings identify a previously unrecognized SIRT6-NCOA2-PPARα signaling axis as a metabolic vulnerability in bladder cancer.

Thiazolidinedione agonists (pioglitazone, rosiglitazone) have modest but clinically significant anti-psoriatic efficacy when combined with traditional systemic medicines, resulting in cardiometabolic benefits. Future directions include patient biomarker stratification, dual/selective agonists (glitazars), and sensible combination with biologics that target tumor necrosis factor-alpha/IL-17/IL-23. This review reframes PPARs as key players in the relationship between psoriasis and metabolic syndrome by synthesizing molecular understanding and clinical data.

By integrating findings from animal models and human epidemiological studies, we further link these molecular perturbations to adverse outcomes such as dyslipidemia, impaired glucose homeostasis, immune dysfunction, and renal carcinogenesis, emphasizing inter-organ crosstalk mediated by metabolic and hormonal networks. Finally, we highlight current knowledge gaps and propose that integrating multi-omics approaches, receptor-specific models, and standardized exposure assessment frameworks will strengthen causal inference and support more predictive risk assessment strategies for PFAS-related health effects.

The therapeutic potential of SHCZF was evaluated in alpha-naphthylisothiocyanate (ANIT)-induced IC rat model, with ursodeoxycholic acid (UDCA) used as positive control...Importantly, GW6471 altered the regulatory effects of SHCZF on MKK4/JNK pathway and bile acid homeostasis. SHCZF improves IC by regulating PPARα-mediated bile acid homeostasis and MKK4/JNK pathway.

Mechanistically, the inhibition of CD47 by clofibrate was dependent on PPARα, as evidenced by its reversal upon PPARα silencing. Together, these results uncover a novel mechanism through which clofibrate restricts tumor immune escape by transcriptional suppression of CD47.

Using our approach, the following phytochemicals, with predicted moderate bioavailability, high GI absorption, and probable binding with insulin resistance targets, are recommended for further in vivo or in vitro validation for insulin resistance activity: boldione (a steroid); aurantiamide acetate and aurantiamide (peptide derivatives); O-ethyl-[(3,4-dihydroxyphenyl)methyl] carbamothioate and O-methyl-N-[(4-hydroxyphenyl)methyl] carbamothioate (thiocarbamates); 4α,6α-dihydroxyeudesman-8β,12-olide (a sesquiterpenoid); sanleng acid and tianshic acid (fatty acid derivatives); 2',5,5',7-tetrahydroxyflavone; 2',3,5,7-tetrahydroxyflavone; and 6-hydroxykaempferol (flavonoids). By combining network centrality measures of targets, using ROC-derived thresholds for docking energies, and considering ubiquity of phytochemicals, our refined network pharmacology approach may aid in discovering key bioactive phytochemicals as potential chemical markers for standardization and differentiation of an herbal drug.

Notably, all hub genes demonstrated strong diagnostic performance, highlighting their potential as sensitive biomarkers of glyphosate exposure. Collectively, this study provides comprehensive insights into gene expression changes associated with glyphosate exposure in hepatoma cells, linking them to hepatic metabolic dysregulation and immune modulation and suggesting a panel of hub genes with potential diagnostic and therapeutic significance.

Here, we show that combining the PI3Kδ inhibitor linperlisib with the pan-peroxisome proliferator-activated receptor (PPAR) agonist chiglitazar, an agent that reprograms tumor metabolism, delivers robust antitumor activity across FL models, including cell-derived and patient-derived xenografts, with a favorable tolerability profile. Compared with monotherapy, the combination consistently achieves superior tumor control in vivo without overt toxicity, supporting its clinical translation potential. Collectively, these data provide a mechanistic rationale for dual targeting of PI3Kδ and PPARα in FL and advocate for clinical evaluation of this combination with FoxO1 as a pharmacodynamic biomarker.

PDAP1 stabilizes HSPA8 mRNA as an RNA-binding protein to activate ERK/MAPK signaling, which further modulates the expressions of the SREBP1 and PPARα, ultimately driving HCC progression and metastasis through fatty acid metabolism reprogramming. Targeting PDAP1 may provide a promising therapeutic strategy for HCC.