Serpin family H member 1 (Heat-shock protein 47) (HSP47)

Serpin family H member 1 (Heat-shock protein 47), or HSP47, is a specialized molecular chaperone residing in the endoplasmic reticulum (ER) that is essential for the maturation and secretion of various types of collagen, particularly type I and III [1, 6]. Unlike general chaperones, it specifically recognizes and binds to the triple-helical procollagen molecules, facilitating proper folding and preventing the aggregation of nascent chains before they are transported to the Golgi apparatus [3, 14]. In pathological states, particularly chronic fibrotic diseases of the lung, liver, and kidney, HSP47 is significantly upregulated, leading to the excessive and disorganized deposition of collagen fibers that characterizes tissue scarring [15, 18]. Beyond its role in fibrosis, it has been implicated in cancer progression by promoting epithelial-mesenchymal transition and remodeling the tumor microenvironment to support metastasis [2, 23]. Therapeutic strategies currently focus on utilizing siRNA-loaded lipid nanoparticles or small molecule inhibitors to disrupt the HSP47-collagen interaction, thereby reducing the fibrotic burden [5, 9, 22]. However, clinical development has faced challenges, including maintaining safety margins to avoid bone-related toxicity or platelet dysfunction, given the protein's fundamental role in physiological collagen homeostasis and thrombus formation [8, 11, 12].

Other names

SERPINH1ColliginCollagen-binding protein 1 (CBP1)Collagen-binding protein 2 (CBP2)gp46AsTP3OI10RA-A47

The primary mechanism of action for drugs targeting this molecule involves the inhibition of its collagen-specific chaperone function or the reduction of its cellular expression. Small interfering RNA (siRNA) therapies, such as BMS-986263, degrade the SERPINH1 mRNA to lower total protein levels, thereby decreasing the folding and secretion of procollagen molecules into the extracellular matrix [5, 22]. Small molecule inhibitors like Col-003 act by competitively binding to the collagen-binding site on the protein within the endoplasmic reticulum, which prevents the stabilization of the procollagen triple helix and induces the degradation of misfolded procollagen [9, 16, 21]. These actions collectively suppress the excessive collagen deposition characteristic of fibrotic diseases and may also modulate tumor microenvironments or platelet activation [8, 16].