Metabolic-endotoxemia, characterized by the translocation of lipopolysaccharide (LPS) from Gram-negative bacteria into the bloodstream, is a key contributor to chronic low-grade inflammation associated with obesity and type 2 diabetes. This condition exacerbates metabolic disruptions by activating Toll-like receptor 4 (TLR4) on macrophages, leading to the release of pro-inflammatory cytokines and subsequent insulin resistance. Eicosapentaenoic acid (EPA; C20:5 (n-3)), an omega-3 polyunsaturated fatty acid, has demonstrated anti-inflammatory and antioxidative properties, but its precise mechanisms of action in mitigating LPS-induced stress remain unclear. This study investigates the pathways through which C20:5 (n-3) alleviates LPS-induced oxidative stress and inflammation in macrophages. C20:5 (n-3) pretreatment significantly reduced LPS-induced inflammatory responses, decreasing IL-1β and IL-6 expression and IL-1β secretion, and lowering the percentage of HLA-DR+ macrophages. C20:5 (n-3) also attenuated ER stress, evidenced by reduced expression of ATF4, DDIT3, HSPA5/GRP78, BIP, and CHOP at both gene and protein levels. Oxidative stress was mitigated, as shown by decreased HIF1α expression, reduced ROS levels, and preservation of mitochondrial membrane potential. Importantly, C20:5 (n-3) increased the expression of PPARα and FABP5 while inhibiting NF-κB activation independently of the TLR4-IRF5 pathway. The protective effects of C20:5 (n-3) was abolished by PPARα inhibition with GW9662, indicating that C20:5 (n-3)'s action is PPARα-dependent. This study highlights the modulatory role of C20:5 (n-3) in alleviating LPS-induced oxidative stress and inflammation in macrophages through activation of the FABP5/PPARα/NF-κB axis, independently of TLR4-IRF5 signaling. These findings reveal a novel mechanism for C20:5 (n-3)'s anti-inflammatory effects and suggest that targeting the FABP5/PPARα pathway may offer therapeutic potential for treating metabolic disorders associated with chronic inflammation.
Copyright © 2025 Haya AlAbduljader et al. Oxidative Medicine and Cellular Longevity published by John Wiley & Sons Ltd.

The interplay between lipid metabolism and immune response in macrophages plays a pivotal role in various infectious diseases, notably tuberculosis (TB). Herein, we illuminate the modulatory effect of heat-killed Mycobacterium tuberculosis (HKMT) on macrophage lipid metabolism and its implications on the inflammatory cascade. Our findings demonstrate that HKMT potently activates the lipid scavenger receptor, CD36, instigating lipid accumulation. While CD36 inhibition mitigated lipid increase, it unexpectedly exacerbated the inflammatory response. Intriguingly, this paradoxical effect was linked to an upregulation of PPARδ. Functional analyses employing PPARδ modulation revealed its central role in regulating both lipid dynamics and inflammation, suggesting it as a potential therapeutic target. Moreover, primary monocytic cells from diabetic individuals, a demographic at amplified risk of TB, exhibited heightened PPARδ expression and inflammation, further underscoring its pathological relevance. Targeting PPARδ in these cells effectively dampened the inflammatory response, offering a promising therapeutic avenue against TB.
© 2024 The Author(s).

The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.
© 2024 The Authors.

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE). This study aimed to identify LN specific-genes and potential therapeutic targets.We performed high-throughput transcriptome sequencing on peripheral blood mononuclear cells (PBMCs) from LN patients. Healthy individuals and SLE patients without LN were used as controls. To validate the sequencing results, qRT-PCR was performed for 5 upregulated and 5 downregulated genes. Furthermore, the effect of the TNFRSF17-targeting drug IBI379 on patient plasma cells and B cells was evaluated by flow cytometry.Our analysis identified 1493 and 205 differential genes in the LN group compared to the control and SLE without LN groups respectively, with 70 genes common to both sets, marking them as LN-specific. These LN-specific genes were significantly enriched in the 'regulation of biological quality' GO term and the cell cycle pathway. Notably, several genes including TNFRSF17 were significantly overexpressed in the kidneys of both LN patients and NZB/W mice. TNFRSF17 levels correlated positively with urinary protein levels, and negatively with complement C3 and C4 levels in LN patients. The TNFRSF17-targeting drug IBI379 effectively induced apoptosis in patient plasma cells without significantly affecting B cells.Our findings suggest that TNFRSF17 could serve as a potential therapeutic target for LN. Moreover, IBI379 is presented as a promising treatment option for LN.Copyright © 2024 Zou, Yang, Ye, Li, Jiang, Xia, Tan, Long and Wang.

Foamy and inflammatory macrophages play pathogenic roles in metabolic disorders. However, the mechanisms that promote foamy and inflammatory macrophage phenotypes under acute-high-fat feeding (AHFF) remain elusive. Herein, we investigated the role of acyl-CoA synthetase-1 (ACSL1) in favoring the foamy/inflammatory phenotype of monocytes/macrophages upon short-term exposure to palmitate or AHFF. Palmitate exposure induced a foamy/inflammatory phenotype in macrophages which was associated with increased ACSL1 expression. Inhibition/knockdown of ACSL1 in macrophages suppressed the foamy/inflammatory phenotype through the inhibition of the CD36-FABP4-p38-PPARδ signaling axis. ACSL1 inhibition/knockdown suppressed macrophage foaming/inflammation after palmitate stimulation by downregulating the FABP4 expression. Similar results were obtained using primary human monocytes. As expected, oral administration of ACSL1 inhibitor triacsin-C in mice before AHFF normalized the inflammatory/foamy phenotype of the circulatory monocytes by suppressing FABP4 expression. Our results reveal that targeting ACSL1 leads to the attenuation of the CD36-FABP4-p38-PPARδ signaling axis, providing a therapeutic strategy to prevent the AHFF-induced macrophage foaming and inflammation.
© 2023 The Author(s).