<p>TMEM16E is a transmembrane protein that functions both as a phospholipid scramblase and a non-selective ion channel, playing a critical role in cellular ion transport and membrane dynamics. Recent studies have shown that the TMEM16E scramblase also facilitates membrane internalization through macropinocytosis. This study investigates the effects of extracellular protons on TMEM16E's scrambling activity and subsequent macropinocytosis under acidic conditions, which are particularly relevant in pathophysiological contexts such as muscular dystrophies and cancers. Our results indicate that TMEM16E-induced macropinocytosis, as evidenced by the internalization of annexin V, is significantly enhanced in acidic environments (pH 5.5). However, the overall number of macropinosomes, assessed using 70&#xa0;kDa dextran, remained unchanged despite variations in extracellular pH. This suggests that TMEM16E-mediated macropinocytosis operates independently of extracellular proton concentrations. Upon extracellular acidification, both TMEM16E scrambling activity and macropinocytosis were rapidly inhibited, leading to a swift decrease in intracellular Ca²⁺ levels compared to physiological conditions. Notably, intracellular Ca²⁺ was cleared more quickly in acidic environments, indicating a regulatory role for the proton-dependent Ca²⁺ clearance pathways. Using wound healing and MTS assays, we demonstrated that TMEM16E expression significantly enhances cell proliferation and survival under acidic conditions. Our findings underscore the importance of TMEM16E-mediated macropinocytosis in maintaining plasma membrane integrity and promoting cell survival, highlighting its role as a crucial signaling pathway in both physiological and pathological contexts.</p>