Crosstalk between neutrophils and hepatic stellate cells in liver injury and repair: Mechanisms and implications

Table 1 Stage-specific operational framework for neutrophil-hepatic stellate cells crosstalk and therapeutic posture

Stage	Clinical/histological window	Dominant cellular-molecular signature	Neutrophil functional output	Therapeutic posture
I Acute injury (hours-days)	ALT/AST ↑↑, no fibrosis	Ly6Ghi infiltration peak; transient MPO-DNA/cit-H3↑; early αSMA induction	Dual: Early cytotoxic; late reparative	Selective: PAD4 inhibition + NLRP3 dampening in early window; preserve late reparative phenotype
II Chronic active fibrosis (months-years)	NLR ↑, FibroScan ≥ 8.5 kPa or ELF ≥ 9.8, F2-F3	Sustained MPO-DNA/cit-H3 ↑; CCL2, CXCL10 ↑; persistent NETs-HSCs loop	Self-amplifying pro-fibrotic	Disrupt loop: COX-2 + NLRP3 + TGFβR1; avoid prolonged NETs ablation
III Cirrhosis/HCC (F4+ tumor)	High NLR, PIVKA-II/AFP ↑	PD-L1+/PLAUR+ TANs; NETs-rich immune-excluded niche	Pro-tumor, immunosuppressive	Combination: PAD4 or NLRP3 + TGFβR1 + ICI; close infection monitoring

ALT: Alanine transaminase; AST: Aspartate aminotransferase; MPO: Myeloperoxidase; PAD4: Peptidylarginine deiminase 4; NLRP3: NOD-like receptor family pyrin domain containing 3; NLR: Neutrophil-to-lymphocyte ratio; NETs: Neutrophil extracellular traps; HSCs: Hepatic stellate cells; COX-2: Cyclooxygenase-2; HCC: Hepatocellular carcinoma; TGFβR1: Transforming growth factor-β receptor 1; ICI: Immune checkpoint inhibitor.

Table 2 Intervention targets for staged management of chronic liver diseases

Intervention layer	Key way	Clinical evidence	Drugs under development	Transformation challenges
NETs-HSCs signal bridging (fibrosis initiation phase)	TLR3/COX-2/PGE2 axis, TLR4-MyD88 axis	The COX-2 inhibitor celecoxib demonstrated anti-fibrotic effects in the MASH model	PAD4 inhibitor GSK484 (preclinical) VDR agonist 16i (preclinical)	Prostaglandin E2 plays a vital physiological role in gastrointestinal mucosal protection and renal blood flow regulation; prolonged systemic inhibition may induce adverse reactions
Inflammation magnification layer (fibrosis amplification phase)	NLRP3 inflammasome	The NLRP3 inhibitor MCC950 alleviates fibrosis in MASH models	Dapansutrile (OLT1177) has demonstrated favourable safety in the treatment of gout	NLRP3 is coupled with tissue repair and antimicrobial immunity; prolonged or excessive suppression may increase infection risk and limit regenerative capacity
HSCs activation locking layer (fibrotic lock-in period)	TGF-β/TGFβR1 (ALK5)	The TGFβR1 inhibitor galunisertib has entered Phase II clinical trials in HCC	Galunisertib (LY2157299), the p38 MAPK inhibitor losmapimod	TGF-β possesses extensive immunomodulatory functions, suppressing potentially unpredictable immune-related adverse events

NETs: Neutrophil extracellular traps; HSCs: Hepatic stellate cells; TLR: Toll-like receptors; COX-2: Cyclooxygenase-2; PGE2: Prostaglandin E2; MASH: Metabolic dysfunction-associated steatohepatitis; PAD4: Peptidylarginine deiminase 4; NLRP3: NOD-like receptor family pyrin domain containing 3; TGF-β: Transforming growth factor-β; TGFβR1: Transforming growth factor-β receptor 1.