Cellular stress is implicated in the progression of lipopolysaccharide (LPS)-evoked acute lung injury (ALI). The goal of this study was to evaluate the effect of oral supplementation with rosiglitazone (RSG), which is an agonist of peroxisome proliferator-activated receptor (PPAR)-γ, on pulmonary inflammatory response, oxidative stress, and endoplasmic reticulum (ER) stress during LPS-evoked ALI in mice. The mice were randomly divided into four groups and orally supplemented with or without RSG (10 mg/kg) once daily for 5 consecutive days before LPS (1 mg/kg) intraperitoneal injection. The mice were sacrificed at 12 h after LPS injection. As expected, LPS-evoked ALI and death were attenuated in mice that were pretreated with RSG. LPS-evoked increase in chemokines (KC, MIP-2, and MCP-1) and proinflammatory cytokines (TNF-α and IL-1β) was inhibited in the mouse lungs by RSG. RSG pretreatment significantly mitigated LPS-evoked nuclear translocation of NF-κB p65 and p50, which regulate inflammatory gene transcription in the lungs. Additionally, LPS-evoked glutathione depletion and lipid peroxidation were alleviated by RSG. The abnormal expression of NADPH oxidases and antioxidant enzymes was restored in the lung tissues by RSG. Further experiments revealed that LPS-evoked upregulation of GRP78, p-IRE1α, and p-EIF2α was blocked by RSG pretreatment. Mechanistically, RSG pretreatment enhanced PPARγ activity in the mouse lungs and bronchial epithelial cells. RSG promoted the interaction between NF-κB p65 and PPARγ in the mouse lungs. Overall, RSG pretreatment protects against LPS-evoked ALI partially through enhancing PPARγ activity and inhibiting the cellular stress response in the mouse lungs.

One of the key regulatory mechanisms in adipose biology is the NAD[+]/SIRT axis, which is disrupted in conditions such as obesity and insulin resistance. In recent years, increasing attention has been directed toward understanding the role of NAD[+] in adipose biology, including through gene expression analyses. However, most published studies have focused on a limited set of preselected genes, and an integrated analysis of genes associated with NAD[+] alterations in adipose tissue is lacking. The aim of this study was to conduct a systematic literature search to identify rodent studies reporting significant modulation of NAD[+] levels in adipose tissue, along with significant changes in gene expression within the same adipose depot. The extracted genes were then subjected to integrative functional bioinformatic analyses to identify significantly enriched canonical pathways, protein-protein interactions, master regulators, and associations with human diseases. We identified 17 studies, from which 113 unique NAD[+]-associated protein coding genes were extracted. Pathway enrichment analysis revealed multiple canonical pathways significantly associated with these genes, including thermogenesis, the PPAR signaling pathway, the AMPK signaling pathway, and adipogenesis. In addition, several cellular pathways were identified for which direct experimental evidence of NAD[+] involvement is currently lacking, such as the apelin signaling pathway and the relaxin signaling pathway. Protein-protein interaction analysis revealed three distinct protein clusters related to positive regulation of cold-induced thermogenesis, inflammation, and cellular respiration. Master regulator analysis identified several well-established regulators, such as leptin, PRDM16, PPARGC1A, AMP, glucose, fructose, and rosiglitazone, as well as regulators that have not yet been directly investigated in the context of NAD[+] function in adipose biology. Finally, analysis of disease associations of NAD[+]-associated protein coding genes revealed links to nutritional and cardiometabolic diseases. In conclusion, this study highlights both well-established and previously unexplored canonical pathways and regulators of biological processes associated with the role of NAD[+] in adipose biology, thereby identifying potential targets for future experimental investigation. Additionally, our systematic literature search revealed a notable lack of studies employing global transcriptomic approaches, as well as multi-omics studies with coupled bioinformatic analyses, which are essential for obtaining an in-depth and comprehensive understanding of the role of NAD[+] in adipose biology.

Breastfeeding reduces the risk of severe lower respiratory infections (sLRIs), a leading cause of infant mortality; however, the protective mechanisms remain elusive. Here, we demonstrated that the absence of milk-derived osteopontin (OPN), highly expressed in colostrum, predisposes neonatal mice to viral and bacterial sLRI, consequent to disrupted dendritic cell (DC) hematopoiesis in the developing liver and lung. Amelioration of disease severity by oral OPN supplementation was associated with increased enteric abundance of Lactobacillaceae and elevated levels of serum 3-phenyllactic acid (PLA), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. Supplementation with PLA or the PPARγ agonist rosiglitazone restored lung DC hematopoiesis via airway epithelium-derived chemokine ligand 25 (CCL25)-mediated recruitment of lymphoid-myeloid primed progenitors and induction of a supportive lung niche. PLA-induced DC hematopoiesis and disease tolerance were attenuated by plasmacytoid DC depletion, immunoneutralization of stem cell factor, or genetic deletion of airway epithelial Flt3L. Our findings elucidate a microbiome-host interaction by which milk OPN confers protection against sLRI.

Peroxisome proliferator-activated receptor gamma (PPARγ), a well-characterized regulator of adipogenesis, also functions as a tumor suppressor in breast cancer. However, the PPARγ agonist rosiglitazone has shown limited clinical efficacy, highlighting the importance of understanding PPARγ regulation within the tumor microenvironment. Here, we demonstrate that adipocyte-derived palmitic acid promotes PPARγ S-palmitoylation via zinc finger DHHC-domain containing protein 15 (ZDHHC15), as confirmed by acyl-biotin exchange (ABE) assay. Immunoblot, RT-qPCR, and immunoprecipitation further revealed that this modification leads to ubiquitin-mediated proteasomal degradation of PPARγ. Functional studies using adipocyte-conditioned media and an oxygen-permeable 3D spheroid culture system showed that PPARγ palmitoylation promotes breast cancer malignancy and confers resistance to rosiglitazone. Notably, the palmitoylation inhibitor 2-bromopalmitate (2-BP) stabilizes PPARγ, suppressing breast cancer malignancy. Furthermore, 2-BP synergistically enhances the therapeutic efficacy of rosiglitazone, suggesting that targeting PPARγ S-palmitoylation represents a promising therapeutic strategy in breast cancer.

The cGAS/STING pathway is a critical signaling hub that orchestrates type I interferon (IFN) responses, autophagy, and programmed cell death in response to double-stranded DNA (dsDNA) or cyclic dinucleotides. While traditionally characterized as a sensor of foreign or mis-localized self dsDNA, recent evidence demonstrates that STING also integrates information about the homeostasis of cellular lipid biosynthesis into the innate inflammatory response. This integration occurs most notably through STING's sensitivity to de novo cholesterol synthesis. However, given that mammalian cells undergo widespread lipid metabolic reprogramming, characterized by alterations in the synthesis of many lipid species in addition to cholesterol, during processes such as malignant transformation to cancer or during infection by intracellular pathogens, we hypothesized that STING function may be regulated by perturbations in other undescribed lipid pathways. To investigate potential other facets of the STING-lipid interface, we have performed a targeted small molecule screen across multiple lipid metabolic pathways, including the mevalonate, PPAR (fatty acid), and arachidonic acid pathways. Our findings reveal that positively and negatively perturbing enzymes within these diverse lipid paths including lipoxygenases and cyclooxygenases can significantly modulate STING-dependent signal transduction and transcriptional programs, identifying metabolic nodes that link lipid homeostasis with innate immune signaling. These results suggest that existing lipid-lowering and metabolic therapies may have unappreciated immunomodulatory effects on STING applicable in cancer and infectious disease, offering new opportunities for therapeutic intervention.

Insufficient responses to available treatments for major depressive disorder (MDD) underscores the necessity for innovative therapeutic strategies. This study investigated the efficacy of adjunctive rosiglitazone, an antidiabetic agent with neuroprotective and anti-inflammatory effects, for MDD. In this 6-week randomized, parallel-group, double-blind, placebo-controlled clinical trial, patients with MDD were assigned to receive sertraline along with either rosiglitazone 2 mg or a matched placebo q12 h. Participants were evaluated using the Hamilton depression rating scale (HDRS) at baseline and weeks 2, 4, and 6. The difference in its score changes to the endpoint was the primary outcome. Side effects were documented as well. The participants had comparable baseline characteristics. A significant time -treatment interaction effect was observed for HDRS scores (η P 2 = 0.052), with the rosiglitazone group experiencing significantly greater reductions at weeks 2 (Cohen's d = 0.507), 4 (Cohen's d = 0.556), and 6 (Cohen's d = 0.541) compared to the placebo group. Additionally, the rosiglitazone group demonstrated significantly higher response rates until weeks 4 (50.0% vs. 24.2%) and 6 (84.4% versus 51.5%). By week 6, the remission rate was nonsignificantly higher in the rosiglitazone group (18.8%) than in the placebo group (9.1%). Side effect frequencies were comparable. In conclusion, rosiglitazone was beneficial for depressive symptoms of patients with MDD safely and tolerably. Further long-term, large-scale studies are recommended to confirm this evidence. Trial Registration: ClinicalTrials.gov identifier: IRCT20090117001556N152.

Psychiatric disorders frequently co-occur with insulin resistance (IR)-related conditions, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS). While genetic correlations have been reported, the genetics underlying this multimorbidity remains underexplored. Here, we investigate the joint genetic architecture of psychiatric-IR multimorbidity and explore links with the brain, tissue-specific gene expression, potential underlying biological mechanisms, and repurposable drugs. Genomic structural equation modeling (SEM) was applied to genome-wide association studies (GWAS) from five psychiatric disorders (attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), schizophrenia) and three IR-related conditions (MetS, obesity, T2DM) (N = 9725-933,970) previously showing pairwise genetic correlations. Factor analyses identified a latent genetic factor (Psych-IR factor) capturing shared genetics across psychiatric disorders (excluding schizophrenia) and IR-related conditions. Positive loadings were observed for ADHD, MDD, and IR-related conditions and negative loadings for AN and OCD. This factor showed genetic correlations with temporal, occipital, and total brain surface areas. A multivariate GWAS of the Psych-IR factor identified 150 associated loci and 366 genes (128 novel). Gene-set associations included insulin binding and Notch-signaling pathways, while gene-property analyses implicated the cerebellum, brain cortex, and pituitary gland, notably during prenatal development. Transcriptome-wide SEM (T-SEM) assessed tissue-specific gene expression associations and identified 499 genes (191 novel), including immune-related genes within the major histocompatibility complex (MHC) region. Drug repurposing analysis suggested six therapeutic candidates, including memantine and rosiglitazone. Enrichment of prioritized genes highlighted the chr16p11.2 region, BDNF-signaling, and lipid metabolism pathways. These findings advance understanding of the genetic and biological mechanisms underpinning psychiatric-IR multimorbidity, informing future research on precision medicine initiatives.

The tarsus is critical for maintaining eyelid structural integrity, functional stability, and ocular surface health. Tarsal defects result in dual impairments of mechanical support and meibomian gland secretion, leading to severe complications such as corneal exposure and epithelial damage. However, current tarsal substitute materials fail to simultaneously meet the requirements of anatomical biomimicry, mechanical compatibility, and functional tissue integration, thereby constituting a significant bottleneck in clinical repair. To address this challenge, we developed a novel biomimetic tarsal microtissue strategy: based on the natural anatomical structure of the tarsus, a structurally zoned gelatin methacryloyl (GelMA) hydrogel scaffold was fabricated via digital light processing (DLP) 3D printing. Its mechanical properties were further enhanced by mechanical stimulation combined with salting-out, achieving a strength and flexibility comparable to those of native tarsal tissue. Subsequently, the scaffold was seeded with rosiglitazone (Rosi)-induced differentiated human meibomian gland epithelial cells (hMGECs) to construct the biomimetic tarsal microtissue. In vitro and in vivo experiments demonstrated that this microtissue exerted excellent substitution effects. When implanted in situ into rat eyelid defects, it effectively provided mechanical support and promoted tissue regeneration. This integrated strategy offers a promising approach to structural reconstruction and clinical functional amelioration of tarsal defects, with significant potential to improve ocular surface health and clinical outcomes for patients.

Hypertriglyceridemic acute pancreatitis (HTG-AP) progresses rapidly with poor prognosis. Intestinal barrier dysfunction and excessive oxidative stress contribute to its pathogenesis, but specific mediators linking gut injury, oxidative stress and pancreatic damage remain unclear. Here, we identify endogenous phenyllactic acid (PLA) as a critical metabolite regulating intestinal barrier integrity and oxidative homeostasis in HTG-AP. We noted serum PLA, a disease-associated metabolite whose reduction correlates with gut dysbiosis and pancreatic inflammation in HTG-AP. PLA supplementation in HTG-AP mice attenuated intestinal barrier dysfunction and mitigated intestinal oxidative stress, as evidenced by improved gut dysbiosis, reduced reactive oxygen species accumulation, restored superoxide dismutase activity, restored barrier integrity, reduced bacterial translocation to the pancreas, and decreased serum lipopolysaccharide levels, ultimately mitigating pancreatic injury. RNA sequencing of colonic tissue revealed peroxisome proliferator-activated receptor (PPAR) signaling as one of the most significantly altered pathways in HTG-AP. PPARγ expression was markedly reduced in colonic epithelial cells and upregulated upon PLA treatment. Knockdown of colonic epithelial PPARγ via adeno-associated virus abrogated the beneficial effects of PLA on intestinal barrier integrity, oxidative stress and pancreatic injury in HTG-AP mice. The protective effects of PLA were phenocopied by the PPARγ agonist rosiglitazone. Collectively, these findings identified gut microbiota-derived PLA as an endogenously derived metabolite modulating intestinal oxidative stress and barrier function. Using male C57BL/6J mice to establish an HTG-AP model, we further revealed that PLA exerts protective effects against HTG-AP by targeting colonic PPARγ to modulate the gut-pancreas axis, highlighting PLA as a promising candidate for targeted intervention in HTG-AP.

Background: Recruitment and activation of monocyte-derived macrophages (MoMFs) sustain cholangitis in primary biliary cholangitis (PBC), but whether MoMFs amplify inflammation through ferroptosis remains unclear. We defined ferroptotic programs in MoMFs and evaluated the calpain/ACSL4 axis as a regulatory and therapeutic node. Methods: We analysed a public human liver single-cell RNA sequencing (scRNA-seq) dataset and examined MoMF-associated ACSL4 and 4-hydroxynonenal (4-HNE) signals in CD11b[+]CD68[+] cells by multiplex immunofluorescence. We used a 2OA-BSA-induced PBC-like mouse model to assess liver injury, inflammation and ferroptosis-related markers and tested Liproxstatin-1 (Lip-1), rosiglitazone (ROSI) or the calpain inhibitor PD150606. Bone marrow-derived macrophages (BMDMs) from control and PBC mice were profiled and challenged with RSL3, with or without Ferrostatin-1 (Fer-1), ROSI or PD150606. Results: MoMFs were expanded in PBC livers and showed the strongest induction of ferroptosis signatures, centered on ACSL4, with enhanced inflammatory crosstalk with cholangiocytes. Human PBC tissues showed increased CD11b[+]CD68[+] cells positive for ACSL4 or 4-HNE. In PBC-like mice, malondialdehyde (MDA) increased and glutathione (GSH) decreased, and macrophages showed greater colocalization with ferroptosis markers; Lip-1, ROSI or PD150606 improved liver biochemistry, reduced inflammation scores and limited macrophage infiltration. PBC-derived BMDMs upregulated ACSL4 and CAPN1/2 and were more sensitive to RSL3; Fer-1, ROSI or PD150606 attenuated ferroptosis-associated molecular changes. Conclusions: MoMF ferroptosis is prominently engaged in PBC, and our findings implicate a pharmacologically tractable calpain/ACSL4 axis that may contribute to macrophage ferroptotic susceptibility and inflammatory liver injury.