Cardiovascular disease (CVD) is one of the leading causes of death and disease burden worldwide. With ongoing shifts in lifestyle patterns, the incidence of CVD is increasing year by year, especially in middle-aged and elderly people [1]. It has been reported that metabolic disorders such as overweight/obesity, insulin resistance, dyslipidemia, etc., are significant risk factors for CVD [2]. In addition, conditions such as diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) frequently coexist with CVD and aggravate one another, forming a pathological cycle that accelerates cardiovascular deterioration and amplifies disease progression [3].

Recently, the role of the angiopoietin-like family (ANGPTLs) in metabolism and cardiovascular diseases has attracted extensive attention. The ANGPTLs are named for their structural similarity to angiopoietin proteins, but lack the necessary structural domains for binding to the classic angiopoietin receptors Tie1 or Tie2, which implies that the functional mechanisms of ANGPTLs may differ from those of angiopoietins [4,5]. The family comprises eight members (ANGPTL1-8), most of which share a conserved structure consisting of an N-terminal signal peptide, a coiled-coil domain, and a C-terminal fibrinogen-like domain. ANGPTL8, identified in 2012, is considered an atypical member, as it lacks the fibrinogen-like domain but retains the N-terminal coiled-coil motif found in ANGPTL3 and ANGPTL4 [6]. Studies have shown that ANGPTL8 plays an important role in lipid metabolism by regulating lipoprotein lipase (LPL) enzyme activity through interaction with ANGPTL3 and ANGPTL4(7). Emerging evidence further implicates ANGPTL8 in glucose metabolism, inflammation, oxidative stress, cell proliferation, and apoptosis, underscoring its broader involvement in the pathogenesis of metabolic and cardiovascular diseases [8]. However, no comprehensive review has systematically summarized the relationship between ANGPTL8 and CVD. Some existing studies suggest that ANGPTL8 may have opposing effects on cardiovascular diseases [9], indicating that it may exert its effects through different signaling pathways. A comprehensive synthesis of current evidence is therefore needed to clarify its functional roles across both metabolic and cardiovascular settings, and to better understand its potential as a molecular bridge linking these disease systems.

In this review, we systematically summarize the regulatory factors influencing ANGPTL8 expression and provide an updated overview of its roles in metabolic disorders and CVD. Particular emphasis is placed on the bidirectional effects and underlying mechanisms of ANGPTL8 in metabolism and cardiovascular diseases, with the goal of advancing an integrated understanding of its contribution to cardiometabolic disorders.