Niemann–Pick C1-Like 1 in Cholesterol Absorption and Homeostasis: Mechanisms, Regulation, and Emerging Phytochemical Inhibitors

Disruption of cholesterol homeostasis is closely associated with hypercholesterolemia, dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and metabolic disorders such as metabolic dysfunction-associated fatty liver disease (MAFLD). Intestinal and hepatic cholesterol absorption are central to maintaining systemic cholesterol balance, with Niemann–Pick C1-Like 1 (NPC1L1) acting as a key transporter that mediates cholesterol uptake in enterocytes and hepatocytes. Aberrant NPC1L1 expression or activity promotes excessive cholesterol accumulation in both plasma and liver, thereby contributing to dyslipidemia and hepatic steatosis. Consequently, NPC1L1 has emerged as an important therapeutic target for reducing cholesterol absorption and improving lipid homeostasis. Although ezetimibe is currently the only clinically approved NPC1L1 inhibitor, its limited efficacy as monotherapy highlights the need for alternative or complementary therapeutic strategies. Growing evidence indicates that natural phytochemicals, particularly polyphenols and flavonoids, can modulate NPC1L1 at both transcriptional and functional levels. These compounds not only suppress intestinal cholesterol absorption but also attenuate hepatic lipid accumulation, ultimately improving circulating lipid profiles. This review summarizes recent advances in understanding the role of NPC1L1 in cholesterol metabolism and highlights the emerging therapeutic potential of phytochemicals as novel complementary approaches for the prevention and treatment of lipid metabolic disorders.