Adipose tissue plays a critical role in obesity, as its dysfunction can impair lipid homeostasis and result in lipid overflow and ectopic lipid deposition in the liver. We previously demonstrated that Isthmin-1 (Ism1) regulates glucose uptake into the adipose tissue and suppresses hepatic steatosis, but the role of adipose-derived Ism1 is unknown. Here, we investigate the role of adipose-derived Ism1 in metabolic health and its impact on hepatic steatosis and lipid metabolism.
In this study, we employed both a genetic knockout approach, selectively deleting Ism1 in adipose tissue of mice (AdipoQ-Ism1-KO), and a pharmacological approach by administering recombinant Ism1 protein to mice. These mice were subjected to a high fat-high fructose diet to simulate conditions that promote Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD).
AdipoQ-Ism1-KO are of normal weight, but prone to severe hepatic steatosis in response to high fat-high fructose feeding. Lipidomic profiling through untargeted analyses in both gain-of-function and loss-of-function models was used to assess changes in hepatic lipid homeostasis. These results provide in vivo genetic support for the role of Ism1 as a regulator of the adipose-hepatic axis.
Collectively, these data demonstrate that loss of adipose-derived Ism1 disrupts lipid homeostasis and accelerates the development of hepatic steatosis. This study provides a genetic basis for Ism1's involvement in metabolic regulation, suggesting a potential therapeutic target for treating metabolic disorders.
Copyright © 2025 The Author(s). Published by Elsevier GmbH.. All rights reserved.

Polydatin (PD), a stilbenoid resveratrol-derivative in Vitaceae, Liliaceae, and Leguminosae, exhibits pharmacological protection in metabolic disorders. This study investigated Polydatin, as a potential pan-PPAR agonist for treating non-alcoholic fatty liver disease (NAFLD). High-throughput-virtual-screening (HTVS) was performed to identify potential pan-PPAR agonists, followed by in vitro testing of Polydatin in HepG2 steatosis model. Effects on lipid metabolism and oxidative stress, PPAR signaling gene expression analysis, and GC-MS profiling were compared with the hepatoprotectant Silymarin. Pan-PPAR targeted HTVS of PhytoHub natural products database, followed by molecular docking/dynamics simulations, revealed lead-candidate, Polydatin, which was tested in steatotic cells for gene and protein deregulations by qRT-PCR and western blot, followed by GC-MS analysis of biochemical metabolites. HTVS revealed 53 potential pan-PPAR agonists. Molecular docking and dynamics simulations suggested that PD, a stable ligand for PPARs (α,β/δ,γ), exhibited strong binding. Polydatin treatment decreased ALT, triglycerides, and oxidative stress, wherein ROS and malondialdehyde levels decreased by 60.94% and 28%, respectively. PD upregulated PPARs, AMPK, GLUT2, and CPT1α, while downregulating lipogenic enzymes (ACC1, FASN, SCD1). GC-MS analysis revealed Polydatin mediated impact on saturated FFAs-palmitic acid, stearic acid, and unsaturated fatty acid product of SCD1, oleic acid. HTVS identified PD as a promising pan-PPAR agonist, which favorably ameliorated changes in lipid, glucose, and overall energy metabolism in steatotic NAFLD, by modulating PPAR(α,β/δ,γ) expressions and associated downstream lipogenic and lipid-utilization mechanisms, supporting anti-steatotic efficacy of Polydatin.
© 2025. The Author(s).

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) pathology and is closely linked to oxidative stress, which contributes to blood-brain barrier leakage, renal dysfunction, and cognitive decline. We investigated the effects of N-acetyl cysteine (NAC), an FDA-approved antioxidant, on oxidative stress, brain Aβ levels, barrier leakage, renal function, and cognition in 5xFAD mice. Eight-week-old 5xFAD mice were fed a rodent diet supplemented with 600 mg/kgDiet NAC for 4 weeks; wild-type (WT) mice and control 5xFAD mice were fed a regular rodent diet. We detected elevated brain and renal 4-hydroxynonenal(4-HNE) levels, reduced creatinine clearance, and increased plasma S100β levels in untreated 5xFAD mice compared to WT controls. Untreated 5xFAD mice also had higher capillary leakage, reduced P-gp activity, and impaired cognition compared to WT. NAC treatment of 5xFAD mice reduced brain Aβ40 levels, normalized 4-HNE levels to control levels, improved creatinine clearance, decreased capillary leakage, and lowered S100β plasma levels. NAC improved cognitive performance in 5xFAD mice, as shown by Y-maze. Our findings indicate that Aβ-induced oxidative stress contributes to barrier dysfunction, renal impairment, and cognitive deficits in 5xFAD mice. Notably, NAC treatment mitigates these effects, suggesting its potential as an adjunct therapy for AD and other Aβ-related pathologies by reducing oxidative stress.

mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for plug-and-play assembly of diverse biodegradable ionizable lipids and identify a lead candidate that produces superior lipid nanoparticles for various gene editing tools delivery in vivo . Our study highlights the utility of this synthetic approach and the generality of this platform for potent in vivo gene editing.

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and GP130 are co-overexpressed in the majority of HER2-enriched breast cancers and TNBCs at 53.8% and 44.4%, respectively. tGLI1+IL-6/IL-6R/GP130 signaling is frequently co-enriched and co-activated in HER2-enriched breast cancer and TNBC when compared to luminal subtypes. tGLI1+GP130 co-overexpression strongly promotes CSCs of HER2-enriched breast cancer and TNBC. FDA-approved tGLI1 inhibitor Ketoconazole and GP130 inhibitor Bazedoxifene synergize against breast cancer proliferation and CSC phenotypes in vitro and reduce TNBC tumor growth and metastatic burden in vivo. Our study demonstrates, for the first time, that co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways is synergistic against HER2-enriched breast cancer and TNBC, warranting future clinical investigations.