Sumit Kumar Anand

Dietary fish oil (FO) and omega-3 fatty acids are associated with cardiometabolic benefits, yet their molecular mediators remain incompletely defined. Furan fatty acids (FuFAs), a distinct lipid class enriched in FO, have emerged as potential regulators of metabolic health. Here, we identify and quantify FuFA species in prescription omega-3 formulations and natural fish oils, and synthesize structurally engineered analogs designed to isolate antioxidant activity and β-oxidation susceptibility from FuFA bioactivity. In a diet-induced obesity mouse model, both natural and synthetic FuFAs reduced fat accumulation and inflammatory markers, while 11U3-2M additionally produced significant improvement in glucose tolerance, dyslipidemia, and hepatic steatosis. The superior activity of 11U3-2M reflects the stable accumulation of its acyl-CoA conjugate that activates peroxisome proliferator-activated receptor alpha (PPARα) signaling and allosterically inhibits acetyl-CoA carboxylases (ACCs) to reprogram hepatic lipid metabolism. These findings position FuFAs as functional dietary lipids contributing to fish oil’s metabolic effects and define fatty acid structural determinants that govern hepatic metabolic activity.

BACKGROUND: Apoptotic cell clearance by macrophages, termed efferocytosis , resolves inflammation and promotes tissue repair, whereas defective efferocytosis contributes to chronic inflammatory diseases such as atherosclerosis. Putrescine biosynthesis, driven by the rate-limiting enzyme ODC1 (ornithine decarboxylase 1), has emerged as a key efferocytosis-induced metabolic pathway that promotes inflammation resolution. However, the mechanisms regulating ODC1 during atherosclerosis remain undefined. Here, we investigated the mechanisms controlling ODC1 and putrescine biosynthesis and identified a novel integrin αv–FAK (focal adhesion kinase)–Rac1 (Rac family small GTPase 1)–STAT3 (signal transducer and activator of transcription 3)–MYC (MYC proto-oncogene) signaling axis that becomes progressively impaired during atherosclerosis. METHODS: We performed metabolomic and cytokine profiling of human atherosclerotic plaques and assessed ODC1 expression in lesional macrophages from humans and mice. Mechanistic studies used apoptotic cell– or polystyrene bead–exposed macrophages, Ldlr ^{–/ –} mice with hematopoietic integrin αv deficiency fed a Western-type diet, single-nuclei RNA sequencing, and bulk RNA sequencing. RESULTS: Putrescine levels negatively correlated with inflammatory mediators, and ODC1 expression in lesional macrophages declined with disease progression in humans and mice. Engulfment of apoptotic cells or polystyrene beads increased ODC1 expression through an integrin αv– and actin polymerization–dependent mechanism. Hematopoietic integrin αv deficiency exacerbated lesion size and necrosis, reduced efferocytosis, and decreased fibrous cap thickness. Single-nuclei RNA sequencing showed no changes in lesional cell composition but revealed activation of inflammatory pathways specifically in integrin αv–deficient macrophages. Mechanistically, phagocytosis-induced ODC1 expression relied on integrin αv–mediated STAT3 activation and MYC-dependent Odc1 transcription. Bulk RNA sequencing showed that apoptotic cell–exposed human macrophages lacking integrin αv upregulated atherogenic mediators and inflammatory pathways, an effect reversed by restoring putrescine levels. CONCLUSIONS: Together, these findings uncover a previously unrecognized mechanistic link between phagocytosis and macrophage metabolism, which we identify as a case of mechanometabolism, and demonstrate how its dysregulation compromises inflammation resolution and promotes atherosclerosis.

BACKGROUND: Neutrophil infiltration exacerbates brain injury after subarachnoid hemorrhage (SAH). Integrin α9, expressed on neutrophils, facilitates their adhesion and transendothelial migration, leading to aggravated inflammatory responses and neuronal apoptosis. Insufficient clearance of apoptotic neurons by microglia and infiltrating blood-derived macrophages (defective efferocytosis) contributes to persistent inflammation and poor SAH recovery. This study investigated the role of neutrophil integrin α9 in neuronal apoptosis, microglia/macrophage efferocytosis, and SAH outcomes. METHODS: Neutrophil-specific α9 ^–/– ( α9 ^fl/fl Mrp8Cre ^–/+ ) and littermate control ( α9 ^fl/fl Mrp8Cre ^–/– ) mice were subjected to the endovascular perforation model to induce SAH. Sensorimotor and cognitive function were assessed for up to 4 weeks post-SAH using neurological severity score, corner and cylinder tests, Y-maze, and novel object recognition. In vitro and in vivo functional assays were conducted to assess the effect of integrin α9–dependent neutrophil transendothelial migration on efferocytosis of apoptotic neurons. Neutrophil infiltration, cerebral inflammation, neuronal apoptosis, and MMP (matrix metalloproteinase)-9 were quantified 24 hours post-SAH. RESULTS: Mice subjected to SAH exhibited increased integrin α9 levels on infiltrated neutrophils compared with sham surgery controls. Neutrophil-specific α9 ^–/– mice demonstrated improved long-term sensorimotor and cognitive recovery, reduced neutrophil infiltration, and decreased MMP-9 expression and neuronal apoptosis. Importantly, neutrophil-specific α9 ^–/– mice exhibited reduced brain neutrophil elastase levels and enhanced efferocytosis. Mechanistic studies have revealed that the reduced transendothelial migration of α9 ^–/– neutrophils directly contributed to the enhanced microglia/macrophage efferocytosis of apoptotic neurons. Pharmacological targeting of integrin α9 with macitentan significantly improved SAH outcomes by reducing neutrophil infiltration and enhancing efferocytosis. Comparable SAH outcomes in both macitentan-treated controls and neutrophil-specific α9 ^–/– mice suggested that the therapeutic effects of macitentan were mediated by inhibition of neutrophil integrin α9. CONCLUSIONS: Our study revealed a novel role for neutrophil integrin α9 in sensorimotor function and cognitive recovery after SAH, suggesting it as a potential therapeutic target for SAH.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing malignancies. Recently, nonalcoholic steatohepatitis (NASH), characterized by liver steatosis, inflammation, cell injury (hepatocyte ballooning), and different stages of fibrosis, has emerged as a major catalyst for HCC. Because the STE20‐type kinases, MST3 and MST4, have been described as critical molecular regulators of NASH pathophysiology, we here focused on determining the relevance of these proteins in human HCC. By analyzing public datasets and in‐house cohorts, we found that hepatic MST3 and MST4 expression was positively correlated with the incidence and severity of HCC. We also found that the silencing of both MST3 and MST4, but also either of them individually, markedly suppressed the tumorigenesis of human HCC cells including attenuated proliferation, migration, invasion, and epithelial‐mesenchymal transition. Mechanistic investigations revealed lower activation of STAT3 signaling in MST3/MST4‐deficient hepatocytes and identified GOLGA2 and STRIPAK complex as the binding partners of both MST3 and MST4. These findings reveal that MST3 and MST4 play a critical role in promoting the progression of HCC and suggest that targeting these kinases may provide a novel strategy for the treatment of liver cancer.