Introduction:
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, characterized by lipid accumulation and inflammatory cell infiltration within the arterial wall. A critical early event in atherogenesis is the formation of macrophage foam cells driven by excessive uptake of oxidized low-density lipoprotein (oxLDL). While cations such as Ca²+ have been extensively studied in this context, the role of Cl- as a regulatory anion in foam cell formation remains poorly understood. The calcium-activated chloride channel TMEM16A plays an important role in many physiological processes. However, its role in macrophages remains unclear.

Material and methods:
Macrophage cells were treated with oxLDL to induce foam cell formation. TMEM16A expression was modulated by siRNA-mediated knockdown or cDNA-driven overexpression, and its activity was pharmacologically inhibited using T16Ainh-A01 and CaCCinh-A01. Expression of scavenger receptor A (SR-A) and CD36, phosphorylation level of JNK, and p38 MAPK signaling pathways were analyzed by Western blotting to elucidate underlying mechanisms.

Results:
OxLDL treatment significantly increased TMEM16A expression in RAW264.7 and THP-1 macrophages. Genetic silencing or pharmacological inhibition of TMEM16A markedly attenuated oxLDL-induced lipid accumulation and foam cell formation, whereas TMEM16A overexpression promoted oxLDL accumulation in macrophages. Mechanistically, TMEM16A deficiency significantly reduced SR-A and CD36 expression, which was associated with decreased phosphorylation of JNK and p38 MAPK, indicating that TMEM16A regulates SR-A and CD36 through a MAPK-dependent signaling pathway.

Conclusions:
These findings demonstrate that TMEM16A plays a critical role in macrophage derived foam cell formation by promoting oxLDL uptake through activation of the JNK/p38–SR-A/CD36 axis. Targeting TMEM16A could be a promising therapeutic strategy for atherosclerosis.