Research progress on the roles of complement in liver injury

Table 1 Complement-associated liver injury

Disease	Complement	Function	Ref.
Hepatic inflammation	C1 inhibitor	Reduce the interaction between white blood cells and endothelial cells in the liver and the expression of VCAM-1	[21]
	C3 deficiency and C3aR/C5aR blockers	Inhibit the complement cascade reaction and reduce liver inflammation	[22]
	Inhibiting C3 or C5	Reduce the 'oxidative burst' induced by bacteria and leukocyte activation, decrease the release of systemic inflammatory mediators	[23]
Alcoholic liver disease	Lacking or inhibit C3, CD55/DAF	Reduce triglyceride accumulation, alleviate liver inflammation caused by inflammatory factors such as TNF-α	[32,33]
	C3a	Upregulating the expression of Gly-tRNA can promote hepatic steatosis	[34]
	C3	Complement factor C3 and lipid regulators have significant interactions in ethanol-induced steatosis	[35]
	C5-deficient	Increased cholesterol deposition in the liver	[36]
Alcoholic hepatitis	C1q	Ethanol activates the classical complement pathway by binding to apoptotic liver cells via C1q, and induces the expression of Tumor Necrosis Factor-alpha and Interleukin-6	[39,40]
	C5aR	Involving the regulation of pro-inflammatory responses by the TLRs/NF-κB signaling pathway	[41-44]
	Factor D	By activating the complement alternative pathway and amplifying in a dependent manner, it alleviates ethanol-induced inflammation and hepatocyte apoptosis	[45,46]
	Inhibition C5aR1	Regulating TLR4 signaling and macrophage polarization	[47]
MASLD/NAFLD	C3	It involves the activation of the complement classical pathway and lectin pathway, mediating neutrophil infiltration	[52,53]
	Lacking C5	Reduced hepatic fat degeneration and lower levels of inflammatory factors	[54]
	C1q	Implicated in the occurrence and development of HCC through activation of the collagen receptor discoidin domain receptor 1	[56]
Viral hepatitis type C	C4	The HCV core gene can inhibit C4 activation	[62]
	C3	HCV proteins can suppress the synthesis of complement C3	[63]
	CD59	Inhibits the formation of MAC, helping the virus to evade the complement system’s attack	[69]
	CH50	Promote the increase in MAC formation	[70]
	C1q	Immune cells accumulate in the liver, activating the complement cascade reaction and producing a large number of C1q–ApoE complexes	[71]
Viral hepatitis type B	MBL	The haplotype frequency of the MBL gene’s exons and promoter region is significantly increased	[72]
	C4, C1q	Complement activation is inhibited, and the formation of C1q is significantly reduced in HBV-ACLF	[73,74]
	CD59	Downregulation of CD59 increases hepatocyte sensitivity to complement-mediated cytotoxicity	[75,76]
	C5a	Inhibit tumor necrosis factor-induced apoptosis of HSCs and participate in liver fibrosis	[9,77]
Chemical liver injury	C3, C3a	Clear apoptotic and necrotic cells and promote the proliferation and regeneration of liver cells	[80]
	C2-FH inhibitor	Inhibition of complement activation can attenuate acetaminophen-induced liver injury in mice	[81]
Autoimmune liver disease	C3	It is related to the pathogenesis of autoimmune liver diseases	[85]
	C4	Participate in autoimmune hepatitis	[86,87]
	DAF, CVF	Inhibit liver injury mediated by excessive complement activation	[89]
	Factor H	Participate in the recurrence and progression of autoimmune hepatitis	[93]
Hepatic IRI	C3a, C5a, and sC5b-9	Play different roles at different time points after liver transplantation	[95]
	C1q	Liver injury caused by increased oxidative stress	[96]
	C6	Locally inhibit the formation of MAC, reduce the expression of inflammatory mediators, and enhance anti-apoptosis	[97]
	sCR1	Improving microvascular circulation and reducing the number of adherent leukocytes	[99]
	C5aR blocker	Reduced the levels of liver enzyme markers serum and tissue inflammatory factors	[100]
	CR2-CD59	Inhibit complement activation and promote liver regeneration.	[101,102]
	Properdin	Improve hepatic IRI by inhibiting the cleavage and activation of C3 and C5	[103]

ACLF: Acute-on-chronic liver failure; CVF: Cobra venom factor; DAF: Decay-accelerating factor; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HSCs: Hepatic stellate cells; IRI: Ischemia–reperfusion injury; MASLD: Metabolic dysfunction-associated steatotic liver disease; MAC: Membrane attack complex; NAFLD: Nonalcoholic fatty liver disease; NF-κB: Nuclear factor kappa B; sCR1: Soluble complement receptors type 1; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-α; VCAM-1: Vascular cell adhesion molecule 1.