The PI3K/AKT signaling pathway is integral to numerous physiological and pathological processes, including cell growth and proliferation, survival and apoptosis, metabolic regulation, angiogenesis, immune response, and cell migration and invasion (5). This pathway plays an essential role in adipogenesis, adipocyte differentiation, and energy storage within adipose tissue (6). In the pancreas, it supports the function and growth of islet β cells. In the muscle tissue, it regulates glucose uptake, protein synthesis, and vasodilation (7).

Activation of this pathway consists of multiple stages. Initially, extracellular signals such as growth factors and hormones bind to receptors on the cell membrane, initiating signal transduction. Receptor activation subsequently activates PI3K, which triggers downstream signaling cascades. PI3K is a heterodimer composed of catalytic subunits (p110α, p110β, p110δ, p110γ) and regulatory subunits (p85α, p55α, p50α, p85β, p55γ, p101, p84, p87). P110α is the main insulin-responsive kinase in adipocytes and muscle ducts, and the localization of p110δ and p110γ isoenzymes is mainly limited to immune cells (8,9). Activated PI3K phosphorylates the precursor protein phosphatidylinositol 4,5-bisphosphate (PIP₂) to phosphatidylinositol (3,4,5)-triphosphate (PIP₃), which acts as a second messenger, and the conversion of PIP₂ to PIP₃ promotes the recruitment of 3-phosphoinositide dependent protein kinase 1 (PDK1) (10). Finally, PDK1 and mammalian rapamycin target protein complex 2 (mTORC2) activate AKT on the membrane. PDK1 completely activates AKT by phosphorylation of the AKT threonine residue at Thr308 and mTORC2 by phosphorylation of AKT's serine residue of AKT at Ser473(11). AKT1 is generally expressed, AKT2 isoenzymes are characteristic in insulin-sensitive tissues (such as muscle, fat and liver tissues), and AKT3 is mostly expressed in the nervous system, pancreas, heart, and kidney (12).

Inhibition of this pathway is orchestrated through multiple mechanisms, including the dephosphorylation of PIP₃ to PIP₂ by phosphatases and inhibitors such as phosphatase and tensin homolog (PTEN), leading to a reduction in PIP₃ levels, a pivotal modulator of AKT activation at the membrane (13). Additionally, negative regulators, such as pro-inflammatory cytokines (including TNF-α and IL-6), transcription factors, and microRNAs, play integral roles in the negative regulation of the pathway (14).

Under physiological conditions, apoptosis is a genetically regulated programmed cell death process that facilitates the timely removal of damaged or dysfunctional cells. It plays a pivotal role in critical biological processes, including development, immune surveillance, and tissue homeostasis, and is indispensable for maintaining cellular equilibrium. Apoptosis serves as a key defense mechanism in the immune system, enabling the elimination of infected cells and irreparable DNA damage (15). The three major apoptotic pathways are the extrinsic death receptor pathway, the intrinsic mitochondrial pathway, and the endoplasmic reticulum pathway, which intersect and interact with one another (16). The hallmarks of apoptosis include cell shrinkage, membrane blebbing, chromatin condensation, formation of apoptotic bodies, and subsequent clearance by phagocytic cells or the immune system (17).

The excessive inhibition or aberrant activation of apoptosis can have deleterious effects. For instance, cancer cells evade normal cell death mechanisms by inhibiting apoptosis, thereby facilitating unchecked cell proliferation (18). In patients with systemic lupus erythematosus, dysregulation of apoptosis prevents the effective clearance of autoantigenic cells, triggering an autoimmune response that attacks self-tissues (19). Research has shown that the adipose tissue in obese mice and humans, induced by high-fat diets, exhibits a pro-apoptotic phenotype. Caspase activation and adipocyte apoptosis are significantly increased, which is considered a key initiating event leading to macrophage infiltration and insulin resistance in obese adipose tissue (20). Furthermore, increased hepatocyte apoptosis has been observed in high-fat diet-induced obese mice, and is recognized as a critical factor in the progression of obesity (21).

Mitochondria, as cellular powerhouses, are central to ATP production and utilize most of the oxygen during oxidative phosphorylation. A small amount of residual oxygen forms superoxide anions, initiating the generation of reactive oxygen species (ROS). Excessive ROS accumulation can trigger mitochondrial swelling, alter membrane permeability, and activate apoptotic pathways by releasing cytochrome c (Cyt c) and other apoptotic factors (22).

Changes in the mitochondrial membrane potential (MMP) is a critical event that initiates apoptosis. Typically, the MMP is maintained at a stable level to support efficient ATP production. However, when cells are subjected to various stressors, the MMP becomes depolarized, which increases membrane permeability. The loss of MMP triggers the release of key pro-apoptotic factors, such as Cyt c, through a process known as mitochondrial outer membrane permeabilization, a key ‘point of no return’ in apoptosis. The B-cell lymphoma 2 (Bcl-2) protein family is integral to MMP regulation. For example, the anti-apoptotic protein, Bcl-2, blocks MMP depolarization, thereby shielding cells from apoptosis (23).

The specific mechanism of mitochondrial pathway activation under obesity is as follows. First, this classical intrinsic apoptotic pathway is triggered by endogenous signals in response to cellular stress or damage (24). Pro-apoptotic members of the Bcl-2 family translocate to the inner mitochondrial membrane, inducing alterations in membrane permeability. These changes facilitate the release of endogenous apoptotic factors such as Cyt c into the cytoplasm. Cyt c binds to the apoptotic protease-activating factor 1 (Apaf-1) to form an apoptosome complex. Formation of the apoptosome activates caspase-9, which in turn activates the downstream effector caspase-3(25). Caspase-3 cleaves multiple cellular substrates and is a key enzyme in apoptosis (Fig. 1). Subsequently, effector caspases degrade critical cellular proteins, leading to membrane blebbing, cell fragmentation into apoptotic bodies, and eventual phagocyte clearance without inducing inflammation. The release of Cyt c and activation of caspases generate a feedback loop in which caspase-3 cleaves anti-apoptotic Bcl-2 proteins, further amplifying Cyt c release and reinforcing the apoptotic cascade (25).

Obesity is strongly associated with the development of various diseases, particularly through its effect on apoptosis, which has been extensively studied. In individuals with obesity, the prevalence of apoptotic cells in the cardiac tissue is higher than that in those with normal weight, which correlates with obesity-induced cardiac remodeling and dysfunction (26). Obesity also contributes to pancreatic β-cell failure, primarily due to increased apoptosis. In addition, the obesity-induced apoptosis of ovarian granulosa cells may affect fertility. Thus, obesity-induced apoptosis is a result of metabolic dysregulation and is a key mechanism in disease pathogenesis (27). The multifactorial mechanisms driving obesity-related apoptosis involve oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lipotoxicity, cytokine signaling, and death receptor activation (Table I).

Obesity disrupts PI3K/AKT signaling through insulin resistance, chronic inflammation, and lipotoxicity. It increases the serine phosphorylation of insulin receptor substrates (IRS), inhibits tyrosine phosphorylation, blocks PI3K p85 binding, and impairs PI3K activation. Serine 307 phosphorylation of IRS-1 is a known marker (28) of insulin resistance. Obesity is often accompanied by chronic low-grade inflammation, characterized by elevated pro-inflammatory cytokines, such as TNF-α and IL-6, intensifying local inflammation and impairing systemic metabolic homeostasis. These cytokines activate signaling pathways, including the mitogen-activated protein kinase (MAPK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways, which can indirectly modulate the PI3K/AKT cascade. Furthermore, they upregulate suppressors of cytokine signaling (SOCS), which bind to IRS, promote IRS degradation, weaken insulin signaling, and ultimately drive metabolic dysfunction. Additionally, high free fatty acids (FFAs) and ceramides induce lipotoxicity: FFAs activate Toll-like receptors (TLRs), aggravating inflammation and insulin resistance, while ceramides inhibit AKT. Moreover, in obesity, adipose tissue secretes various adipokines, such as adiponectin and leptin, which modulate PI3K/AKT pathway activity and influence cellular insulin sensitivity (29). Finally, obesity upregulates microRNAs, such as miR-221, which suppress PI3K and increase insulin resistance (30).

These aforementioned pathways modulate the PI3K/AKT signaling cascade through interactions with cell surface receptors, principally engaging receptor tyrosine kinases (RTKs), TLRs, and B-cell antigen receptors (BCRs). RTKs (31), including epidermal growth factor receptors (EGFRs), vascular endothelial growth factor receptors (VEGFRs), and fibroblast growth factor receptors (FGFRs), are activated by ligands such as growth factors, cytokines, and hormones. The BCR is essential for B cell development, activation, and differentiation, and activates downstream pathways through B-cell receptor-associated protein (BCAP). Additionally, G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, activate specific signaling cascades by recognizing and responding to a wide variety of ligands (32).

Flavonoids, including quercetin (33), kaempferol (34), and puerarin (35); terpenoids, such as astragaloside IV (36) and ginsenoside Rb2(37); and alkaloids, such as capsaicin (38) and berberine (39), regulate glucose and lipid metabolism, facilitate weight loss, and exert anti-inflammatory effects by modulating the PI3K/AKT signaling pathway (Table II). Glinides, a class of drugs that are frequently used in endocrinology, enhance insulin secretion and ameliorate insulin resistance by activating the PI3K/AKT pathway (40). Buparlisib, which is used to treat cancer, functions as a pan-PI3K inhibitor and improves obesity-related metabolic disorders (41).

The PI3K/AKT pathway is a critical signaling cascade that regulates mitochondrial apoptosis by modulating the expression of various proteins, including members of the Bcl-2, Bax, Bad, and caspase families (Fig. 1).

AKT regulates mitochondrial membrane permeability by influencing the Bcl-2 family proteins and Bad. It enhances the anti-apoptotic functions of the Bcl-2 family members, such as Bcl-2 and Bcl-xL, through phosphorylation (42). At the same time, AKT inhibits the pro-apoptotic activity of proteins such as Bax and Bak, preventing their ability to form membrane pores. This reduces the release of mitochondrial apoptotic signals such as Cyt c and diminishes apoptotic body formation. Additionally, AKT phosphorylates Bad, facilitating its binding to 14-3-3 proteins, which reduces competition with Bcl-2/Bcl-xL, further stabilizing the mitochondrial membrane and reinforcing its anti-apoptotic function. Furthermore, AKT activates mTORC1, thereby improving the cellular energy supply. Mitochondrial function is preserved by upregulating antioxidant enzymes such as SOD2, thereby reducing oxidative stress-induced mitochondrial damage (43).

Research has demonstrated that the activation of the PI3K/AKT pathway effectively inhibits apoptosis and promotes cell growth and proliferation. In numerous types of cancer, the aberrant activation of this pathway enables tumor cells to bypass normal apoptotic mechanisms, facilitating sustained tumor growth and metastasis. Research has confirmed that astragaloside IV (44), tanshinone IIA (15), and curcumin (45) modulate mitochondrial apoptosis by regulating the PI3K/AKT pathway. Benazepril, a commonly prescribed antihypertensive agent used for cardiovascular diseases, indirectly alleviates PI3K/AKT pathway dysregulation and mitochondrial dysfunction by lowering blood pressure and improving cardiac function (46). Gefitinib, an EGFR inhibitor, promotes apoptosis in cancer cells by downregulating the PI3K/AKT signaling cascade (47). Additionally, MK-2206, a selective AKT inhibitor, directly induces apoptosis in cells (48).