Fig. 4

Diagram of HSPs in the core apoptotic signaling pathway in cancer. Extrinsic and intrinsic pathways primarily regulate apoptosis. In the extrinsic pathway, upon ligand activation, death receptors recruit critical proteins such as FADD and procaspase-8, forming the death-inducing signaling complex (DISC). Subsequently, caspase-8 and downstream caspases-3/7 are activated, ultimately inducing apoptosis. The intrinsic pathway, also known as the mitochondrial pathway, is receptor-independent. When cells encounter DNA damage or oxidative stress, the balance of Bcl-2 family proteins shifts, with pro-apoptotic proteins (e.g., Bax and Bak) upregulated, and anti-apoptotic proteins (e.g., Bcl-2 and Bcl-xL) downregulated. These changes further lead to mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release. Released cytochrome c binds to apoptotic protease activating factor-1 (Apaf-1), forming the apoptosome, activating the caspase cascade, leading to apoptosis. Additionally, mitochondrial-released proteins such as SMAC/DIABLO and Htra2/Omi can inhibit the activity of XIAP, thereby reducing the apoptotic inhibition caused by XIAP's inhibition of caspase-9. There is also a crosstalk between the intrinsic and extrinsic pathways. Caspase-8 can also cleave Bid into tBid to directly participate in mitochondria-dependent apoptosis. Furthermore, MAPK signaling, PI3K signaling, and endoplasmic reticulum stress can also induce apoptosis. HSPs have been shown to participate in the regulation of apoptotic signaling pathways through various mechanisms. HSP90 maintains the stability and function of many proteins, such as Bcl-xL and PI3K, thereby strengthening the signal transduction of its pathway and inhibiting tumor apoptosis. HSP70 regulates apoptosis through multiple pathways by modulating XIAP, caspases-3/-7/-9, Fas, Bim, and endoplasmic reticulum stability. Moreover, HSP27 has been shown to inhibit apoptosis induced by both intrinsic and extrinsic pathways by blocking the pro-apoptotic actions of Fas and Bax. Additionally, HSP60 and mortalin interact with survivin and p53 to inhibit mitochondria-dependent apoptosis, thereby promoting tumor progression