Tafolecimab mitigates ox‑LDL‑induced macrophage foam cell formation and inflammation by modulating SR‑A/ABCG1 expression and inhibiting the NF‑κB/MAPK pathways

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Macrophage foam-cell formation, triggered by excessive uptake of oxidized low-density lipoprotein (ox-LDL) and subsequent intracellular lipid accumulation, represents a critical pathological event in atherosclerotic plaque initiation that drives localized inflammatory responses.The present study investigated the effects of tafolecimab on ox-LDL-induced foam-cell formation and inflammatory responses in murine macrophages, and further explored the underlying molecular mechanisms.Foam-cell models were established by exposing RAW264.7 cells to 100 µg/ml ox-LDL for 24 h.The study groups included a blank control group, a model group, low-, medium-and high-dose tafolecimab groups (5, 10 and 20 µmol/l, respectively), and a positive control group treated with evolocumab.Intracellular lipid accumulation and cholesterol levels were evaluated using Oil Red O staining and a low-density lipoprotein-cholesterol (LDL-C) assay kit.Western blot analysis was performed to determine the expression of cholesterol metabolism-related proteins [class A scavenger receptor (SR-A) and ATP-binding cassette subfamily G member 1 (ABCG1)] and key components of the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathways (NF-κB p65 and phosphorylated p38).The concentrations of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the cell supernatant were quantified by enzyme-linked immunosorbent assay.Compared with the blank control, ox-LDL treatment markedly increased intracellular lipid-droplet accumulation and LDL-C content, confirming the successful establishment of a foam-cell model.In vitro, compared with the model group, tafolecimab reduced intracellular lipid accumulation and cholesterol content in a dose-dependent manner (P<0.001).In addition, tafolecimab significantly decreased the expression of the cholesterol influx receptor SR-A while increasing that of the cholesterol efflux transporter ABCG1 (P<0.001).Furthermore, it effectively inhibited the phosphorylation of NF-κB p65 and MAPK p38, which was accompanied by reduced secretion of TNF-α and IL-6 (P<0.001).The present results indicate that tafolecimab inhibits ox-LDL-induced macrophage foam-cell formation and inflammatory responses, likely by modulating the balance between SR-A-mediated cholesterol influx and ABCG1-mediated cholesterol efflux in favor of cholesterol efflux, and by inhibiting NF-κB and MAPK pathway activation.

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