{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Complement component 9 (C9) is the terminal, pore‐forming subunit of the membrane attack complex (MAC), a central effector of the complement system responsible for lysing target cells and pathogens. Structural studies demonstrate that once C5b–8 is formed on a target membrane, multiple C9 monomers are sequentially recruited and undergo a conformational change that enables their polymerization into a ring‐shaped pore, thereby compromising membrane integrity and leading to cell lysis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic analyses have uncovered rare C9 variants that affect its secretion and polymerization kinetics. Some of these variants are associated with diseases such as age‐related macular degeneration, indicating that even subtle alterations in C9 polymerization may modulate MAC activity and contribute to disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, intracellular chaperones (for example, mortalin and Hsp90) have been shown to bind C9 and inhibit its polymerization. This interaction reduces complement‐dependent cytotoxicity and may allow cancer cells to evade immune clearance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n C9 also plays a critical role in innate immunity beyond its lytic function. Studies in teleost fish reveal that C9 expression is upregulated in response to bacterial challenge and is essential for effective bactericidal activity, underscoring its conserved role in host defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Clinically, aberrant C9 levels have been documented in a range of human disorders. Altered serum or tissue concentrations of C9 have been proposed as potential biomarkers for various cancers and inflammatory pathologies, while C9 deficiency can predispose to immunologic dysregulation, as evidenced by its association with recurrent miscarriages."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, the collected data emphasize the multifaceted roles of C9—from mediating pore formation and target cell lysis to serving as a modulated player in innate immunity and a clinically useful biomarker. The regulation of its polymerization, whether by genetic variation or by interaction with intracellular chaperones, is critical in determining the extent of complement-mediated cytotoxicity, with implications for infections, cancer, autoimmune and degenerative diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bradley A Spicer, Ruby H P Law, Tom T Caradoc-Davies, et al. 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