Endogenous metabolites as active drivers of acute pancreatitis: Mechanisms and advances in targeted therapy

Table 1 Phase-specific integrated intervention framework for the metabolic network in acute pancreatitis

Disease phase	Intervention level	Representative strategies	Design rationale
Injury initiation phase (approximately 0-6 hours)	Upstream blockade (source)	UDCA/TUDCA (“protective effects of hydrophilic bile acids”) + taurine (“multifaceted protective effects of taurine”)	Hydrophilic bile acids dilute cytotoxic components while taurine stabilizes Ca2+, providing dual buffering at the source of injury
	Downstream priming (early protection)	NAC (“reconstitution of the GSH system”) + early SPMs (“SPM supplementation and optimization of delivery”)	Pre-stocks GSH antioxidant capacity and deploys pro-resolving signals before the pro-inflammatory storm
Inflammation amplification phase (approximately 6-48 hours)	Upstream: DAMP-signal interruption	Allopurinol/febuxostat (“XO inhibition”) + P2X7 antagonist (“P2X7 receptor antagonism and NLRP3 inflammasome blockade”)	XO inhibition lowers ROS and uric acid; P2X7 antagonism interrupts eATP-NLRP3 signaling
	Midstream: Inflammasome-antioxidant axis	MCC950 (“P2X7 receptor antagonism and NLRP3 inflammasome blockade”) + 4-OI (“activation of the Nrf2-antioxidant response elements pathway”)	Direct blockade of NLRP3 assembly plus Nrf2 activation to attenuate upstream oxidative injury
	Collateral: Gut-pancreas axis protection	Targeted butyrate delivery (“supplementation and delivery optimization of butyrate and its derivatives”) + FXR agonist (“targeting FXR and TGR5”)	Butyrate and FXR jointly repair the intestinal barrier, blocking the second hit of bacterial/LPS translocation
	Phase-sensitive strategy	e.g., short-course tryptophan-pathway inhibition [“tryptophan metabolic pathways in AP (the KP and 5-HT pathways)”]	Brief inhibition during the SIRS phase blocks tryptophan-depletion driven immune dysregulation; a defined stop point is required, as prolonged inhibition may impair later immune tolerance
Immune repair phase (approximately after 48 hours)	Macrophage-polarization reprogramming	Sustained SPMs supplementation (“SPM supplementation and optimization of delivery”) + butyrate/HDAC inhibition (“multiple protective mechanisms of butyrate”) + lactate-histone lactylation (see “lactate metabolism and protein lactylation”)	SPMs supplementation, butyrate-mediated HDAC inhibition, and lactate-driven lactylation jointly drive reparative macrophage polarization
	Restoration of the triple messengers	Combined butyrate- and indole-producing probiotics (“supplementation and delivery optimization of butyrate and its derivatives”/“translational potential and limitations of indole-targeted therapies”/“targeting the gut microbiota-bile acid metabolic axis”)	Synchronous restoration of the three messengers SCFAs, secondary bile acids, and indoles to break the vicious cycle; note that PROPATRIA showed multi-strain live probiotics increased mortality
	Reconstruction of energy homeostasis	NR supplementation (“NAD+ supplementation”) + olaparib/PARP inhibition (“NAD+ supplementation”)	Olaparib inhibits PARP to curb NAD+ consumption, while NR supplies precursors to increase NAD+ availability
	Phase switch	Discontinuation of tryptophan-pathway inhibition [“tryptophan metabolic pathways in AP (the KP and 5-HT pathways)”, “immune repair phase (approximately after 48 hours)”]	Withdrawal after the SIRS peak restores the kynurenine-AhR axis, promotes Treg/IL-10 generation, and establishes immune tolerance

The time windows (e.g., approximately 0-6 hours) are based primarily on the tempo of pathological progression in animal experiments and should be regarded clinically as approximate references rather than precise boundaries; they require individualized calibration according to the dynamic changes of indicators such as C-reactive protein, interleukin-6, bedside index for severity in acute pancreatitis/sequential organ failure assessment, and procalcitonin (see “design rationale for phase-based combined intervention” for details). DAMP: Damage-associated molecular pattern; UDCA: Ursodeoxycholic acid; TUDCA: Tauroursodeoxycholic acid; NAC: N-acetylcysteine; GSH: Glutathione; SPMs: Specialized pro-resolving mediators; XO: Xanthine oxidase; P2X7: P2X purinoceptor 7; NLRP3: NOD-like receptor thermal protein domain associated protein 3; 4-OI: 4-octyl itaconate; Nrf2: Nuclear factor erythroid 2-related factor 2; FXR: Farnesoid X receptor; TGR5: Takeda G protein-coupled receptor 5; AP: Acute pancreatitis; KP: Kynurenine pathway; 5-HT: 5-hydroxytryptamine; HDAC: Histone deacetylase; LPS: Lipopolysaccharide; NAD⁺: Nicotinamide adenine dinucleotide; PARP: Poly-adenosine diphosphate ribose polymerase; Ca²⁺: Calcium ion; ROS: Reactive oxygen species; eATP: Extracellular adenosine triphosphate; SIRS: Systemic inflammatory response syndrome; SCFA: Short-chain fatty acid; AhR: Aryl hydrocarbon receptor; Treg: Regulatory T cell; IL: Interleukin; NR: Nicotinamide riboside.