Jianyu Yu

Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Herein, we identify a FABP4–PD-L1 axis that links lipid metabolism to immune checkpoint regulation in myeloid cells. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive splenic macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) was shown to induce FABP4 and promote PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 was essential for this process, which enabled PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16⁺ monocyte population exhibited elevated FABP4–PD-L1 signaling and correlated with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting FABP4 as a potential therapeutic target in cancer immunotherapy.

Saturated fats in high-fat diets (HFDs) have been associated with increased risk and severity of psoriasis. However, the underlying cellular and molecular mechanisms remain to be further defined. Here, using a unique mouse strain with keratinocyte-specific deletion of fatty acid-binding protein 5 (FABP5) (Fabp5 ^f/f Krt6a-Cre), we reported that keratinocyte FABP5 deletion significantly attenuated saturated HFD-exacerbated psoriatic symptoms. Immunological analyses demonstrated that FABP5 specific deletion in keratinocytes selectively reduced skin TCR γ δ ^dim cell accumulation and IL-17A production. Further skin bulk-RNA and single-cell RNA sequence analyses showed a strong association of keratinocyte FABP5 with increased activation of mitogen-activated protein kinase (MAPK) pathways under saturated HFD-induced obesity. Mechanistically, saturated fatty-acids (SFAs) induce FABP5-dependent MAPK activation and CCL20 production in keratinocytes, promoting the recruitment and activation of IL-17-producing γδ T cells in the skin. Together, these findings suggest a previously undefined FABP5/MAPK/CCL20 signaling axis that links saturated fats to exacerbated psoriatic inflammation.

Summary: Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Here, we identify a FABP4–PD-L1 axis that links lipid metabolism to immune checkpoint regulation in monocytes and macrophages. Single-cell transcriptomics revealed a distinct FABP4 ^high immunosuppressive macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) induces FABP4 and promotes PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 is essential for this process, which enables PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14 ^int CD16⁺ monocyte population exhibits elevated FABP4–PD-L1 signaling and correlates with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting that targeting FABP4 may enhance responses to immune checkpoint blockade. Graphical Highlights: FABP4 defines a lipid-responsive, immunosuppressive monocyte/macrophage subset FABP4 links lipid sensing to PD-L1 expression in macrophages FABP4 enables palmitic acid-dependent PD-L1 palmitoylation and stabilization FABP4–PD-L1 signaling correlates with obesity and invasive breast cancer in humans

Summary: Obesity is a major driver of hepatic steatosis, yet the molecular link between excess adiposity and hepatocellular lipid accumulation remains incompletely defined. Here, we identify circulating fatty acid–binding protein 4 (FABP4) as a key mediator of adipocyte–hepatocyte lipid crosstalk in obesity. Analyses of human liver specimens and mouse models reveal aberrant accumulation of FABP4 protein—but not transcript—in hepatocytes during steatosis, indicating an extrinsic source. Genetic deletion of FABP4, specifically in adipocytes, protects against high fat diet-induced hepatic steatosis without altering obesity or systemic lipid levels. Mechanistically, circulating FABP4 directly binds to hepatocytes, facilitating free fatty acid uptake. Furthermore, we developed a high-affinity humanized monoclonal antibody that selectively neutralizes circulating FABP4, blocks hepatocyte binding, suppresses fatty acid uptake, and markedly attenuates hepatic steatosis in multiple obese mouse models. These findings establish circulating FABP4 as a pathogenic lipid chaperone and a promising therapeutic target for obesity-associated hepatic steatosis. Graphical Highlights: Hepatocytic accumulation of extrinsic FABP4 links adiposity to liver lipid deposition. Specific deletion of FABP4 in adipocytes prevents hepatic steatosis without affecting systemic lipid levels or obesity. Circulating FABP4 derived from adipocytes directly binds hepatocytes to facilitate free fatty acid transfer. Blocking circulating FABP4 with a high-affinity anti-FABP4 monoclonal antibody inhibits hepatocyte lipid uptake and attenuates steatosis in multiple obese mouse models.

FABP5 mediates lipid incorporation

Obesity is strongly associated with triple-negative breast cancer (TNBC). A better understanding of the molecular mechanisms driving obesity-induced TNBC progression could facilitate the development of precision dietary intervention strategies. In this study, we used murine models of obesity induced by different high-fat diets (HFD) to examine their impact on TNBC progression. Compared with a low-fat diet, both cocoa butter and olive oil HFDs induced similar levels of obesity. However, only the olive oil HFD–induced obesity increased TNBC stemness and lung metastasis. Mechanistically, oleic acid (OA) in the olive oil HFD facilitated TNBC metastasis by activating the protein kinase C (PKC)–aldehyde dehydrogenase (ALDH) pathway. Furthermore, fatty acid–binding protein 5 (FABP5) in TNBC cells was identified as essential for OA-mediated PKC–ALDH pathway activation. FABP5 deficiency reduced TNBC metastasis in multiple mouse models, whereas higher FABP5 expression correlated with worse outcomes of TNBC in various human studies. These findings collectively suggest that the consumption of olive oil HFD promotes obesity-associated TNBC metastasis through OA/FABP5-driven oncogenic signaling.Significance:Comparison of obesity induced by different high-fat diets revealed that an olive oil-based diet promotes triple-negative breast cancer metastasis by activating FABP5/PKC/ALDH signaling, providing a target for the development of obesity-associated cancer therapeutics.

HFD-associated immunophenotypes