Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor α–positive ( Pdgfra ⁺ ) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and Pdgfra ^GFP lineage tracing to generate a transcriptomic profile of Pdgfra ⁺ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra ⁺ fibroblast–supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra ⁺ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.

Pulmonary fibrosis (PF) is a heterogeneous disease with a poor prognosis. Therefore, identifying additional therapeutic modalities is required to improve outcome. However, the lack of biomarkers of disease progression hampers the preclinical to clinical translational process. Here, this work assesses and identifies progressive alterations in pulmonary function, transcriptomics, and metabolomics in the mouse lung at 7, 14, 21, and 28 days after a single dose of oropharyngeal bleomycin. By integrating multi‐omics data, this work identifies two central gene subnetworks associated with multiple critical pathological changes in transcriptomics and metabolomics as well as pulmonary function. This work presents a multi‐omics‐based framework to establish a translational link between the bleomycin‐induced PF model in mice and human idiopathic pulmonary fibrosis to identify druggable targets and test therapeutic candidates. This work also indicates peripheral cannabinoid receptor 1 (CB₁R) antagonism as a rational therapeutic target for clinical translation in PF. Mouse Lung Fibrosis Atlas can be accessed freely at https://niaaa.nih.gov/mouselungfibrosisatlas.

Significance Statement: This study sheds light on the central role of adenine nucleotide translocase 2 (ANT2) in the pathogenesis of obesity-induced CKD. Our data demonstrate that ANT2 depletion in renal proximal tubule cells (RPTCs) leads to a shift in their primary metabolic program from fatty acid oxidation to aerobic glycolysis, resulting in mitochondrial protection, cellular survival, and preservation of renal function. These findings provide new insights into the underlying mechanisms of obesity-induced CKD and have the potential to be translated toward the development of targeted therapeutic strategies for this debilitating condition. Background: The impairment in ATP production and transport in RPTCs has been linked to the pathogenesis of obesity-induced CKD. This condition is characterized by kidney dysfunction, inflammation, lipotoxicity, and fibrosis. In this study, we investigated the role of ANT2, which serves as the primary regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD. Methods: We generated RPTC-specific ANT2 knockout (RPTC-ANT2 ^−/−) mice, which were then subjected to a 24-week high-fat diet–feeding regimen. We conducted comprehensive assessment of renal morphology, function, and metabolic alterations of these mice. In addition, we used large-scale transcriptomics, proteomics, and metabolomics analyses to gain insights into the role of ANT2 in regulating mitochondrial function, RPTC physiology, and overall renal health. Results: Our findings revealed that obese RPTC-ANT2 ^−/− mice displayed preserved renal morphology and function, along with a notable absence of kidney lipotoxicity and fibrosis. The depletion of Ant2 in RPTCs led to a fundamental rewiring of their primary metabolic program. Specifically, these cells shifted from oxidizing fatty acids as their primary energy source to favoring aerobic glycolysis, a phenomenon mediated by the testis-selective Ant4. Conclusions: We propose a significant role for RPTC-Ant2 in the development of obesity-induced CKD. The nullification of RPTC-Ant2 triggers a cascade of cellular mechanisms, including mitochondrial protection, enhanced RPTC survival, and ultimately the preservation of kidney function. These findings shed new light on the complex metabolic pathways contributing to CKD development and suggest potential therapeutic targets for this condition.

It is well established that prebiotics have a profound influence on colonic microbiota which in turn play an essential role in ameliorating the host’s health. This study is focused on Gum Odina (GO), a reported prebiotic in our earlier work, and its impact on colorectal cancer (CRC). GO, upon utilization by probiotics, liberates short-chain fatty acids, acetic acid (0.864 ± 0.050 mg ml⁻¹) and butyric acid (2.303 ± 0.083 mg ml⁻¹) predominantly and increases colonization of Lactobacillus sp. and Bifidobacterium sp. in a gut simulator. The in vivo preventive study of CRC was conducted on Swiss albino mice using 1,2-dimethyl hydrazine (DMH) along with inulin and GO as the standard and test prebiotic, respectively. Scanning electron micrographs of the colon depict that the severity of mucosal dysplasia, flat lesions and loss of goblet cells was quite low in the GO group compared to the DMH alone treated group. The same was noticed in the histomicrograph in terms of alteration of the colonic architecture and abnormalities in the submucosa. Administration of DMH also caused oxidative burst as the levels of reactive oxygen species and lipid peroxidation significantly increased (p < 0.05) but reduced by 29.35% and 27.65%, respectively, in the GO group. Moreover, the levels of glutathione, glutathione-S-transferase, superoxide dismutase and catalase in the colonic tissues significantly increased (p < 0.05) by 31.26%, 10.96%, 12.4% and 6.37%, respectively, when compared to IN, a standard prebiotic. Thus, GO possesses CRC-preventing along with antioxidant properties and slows the overall tumor genesis process.

Pulmonary fibrosis (PF) is a life-threatening disease that requires effective and well-tolerated therapeutic modalities. Previously, the distinct pathogenic roles of cannabinoid receptor 1 (CB ₁ R) and inducible nitric oxide synthase (iNOS) in the lungs and their joint therapeutic targeting were highlighted in PF. However, the cell-specific role of CB ₁ R in PF has not been explored. Here, we demonstrate that CB ₁ R in alveolar macrophages (AMs) mediates the release of anandamide into the alveoli, which promotes PF by inducing pro-fibrotic macrophages that are accessible to locally delivered antifibrotic therapy. A multitargeted therapy may improve therapeutic efficacy in PF. Pulmonary delivery of 0.5 mg/kg/d MRI-1867 (zevaquenabant), a peripherally acting hybrid CB ₁ R/iNOS inhibitor, was as effective as systemic delivery of 10 mg/kg/d and also matched the efficacy of nintedanib in mitigating bleomycin-induced PF. A systems pharmacology approach revealed that zevaquenabant and nintedanib treatments reversed pathologic changes in both distinct and shared PF-related pathways, which are conserved in human and mouse. Moreover, zevaquenabant treatment also attenuated fibrosis and pro-fibrotic mediators in human precision-cut lung slices. These findings establish CB ₁ R-expressing AMs as a therapeutic target and support local delivery of dual CB ₁ R/iNOS inhibitor zevaquenabant by inhalation as an effective, well-tolerated, and safe strategy for PF.

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.