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.

Table 2 Evidence stratification and translational priority of metabolite-targeted intervention strategies in acute pancreatitis

Tier	Strategy	Target pathway	Evidence nature and context	Key limitations/caveats	Ref.
Tier 1: Human therapeutic evidence	Glutamine	Amino acid metabolism (“targeting glutamine and protection of the gut-pancreas axis”)	Human therapeutic (RCT/meta-analysis; adjunct to parenteral nutrition in severe AP) + animal therapeutic multiple models3	Hard endpoints (infected necrosis, mortality) not consistently improved; trials small, heterogeneous, high risk of bias	Yong et al[89]; Arutla et al[90]; Tao et al[91]
	Ondansetron	5-HT pathway (“modulation of the 5-HT pathway”)	Human therapeutic (retrospective cohort associative) + animal therapeutic multiple models; antiemetic use well established, safety known	Survival signal only from a single-center retrospective study with indication confounding; needs prospective RCT	Tsukamoto et al[74]; Wu et al[75]
Tier 2: Human data available, but not therapeutic evidence in established AP	Olaparib	NAD+ metabolic repair (“NAD+ supplementation”)	Animal therapeutic multiple models + safety from another indication (approved in oncology)1; PAR accumulation in human samples (mechanistic relevance)	No human efficacy data in AP (only PAR accumulation in human samples)	Ahmad et al[77]; Mota et al[78]
	Montelukast	Pro-inflammatory lipid-mediator inhibition (“targeting the LXA4 pathway and modulating pro-inflammatory mediators”)	Animal therapeutic multiple models + safety from another indication (approved for asthma)	No clinical trial for an AP indication	Ozkan et al[37]
	Clostridium butyricum	Microbiota-SCFAs axis (“supplementation and delivery optimization of butyrate and its derivatives”)	Animal therapeutic multiple models + safety from another indication (approved for microbiota modulation)	Poor acute-phase colonization; no clinical efficacy data; live-probiotic safety caution (PROPATRIA)4	Zhao et al[134]; Xiong et al[136]
	UDCA/TUDCA	Bile acid metabolism (“protective effects of hydrophilic bile acids”)	Animal therapeutic multiple models + human prophylaxis (small prospective study) + safety from other indications (approved for gallstone disease/PBC)	AP evidence limited to small prophylactic studies; no treatment evidence in established AP2; needs multicenter RCTs	Seyhun et al[146]; Hall et al[156]; Maringhini et al[157]
	NAC	GSH-system reconstruction (“reconstitution of the GSH system”)	Animal therapeutic multiple models + human prophylaxis (post-ERCP; one small positive RCT, but most RCTs negative)	Positive in one early small RCT only; pooled/meta-analysis data show no clear preventive effect	Minati et al[109]; Yagci et al[110]; Alavi Nejad et al[111]; Tenório et al[112]
	Allopurinol/febuxostat	XO-ROS-uric acid axis (“XO inhibition”)	Animal therapeutic multiple models + safety from another indication (approved for hyperuricemia); human prophylaxis (post-ERCP RCTs negative)	Post-ERCP prophylaxis RCTs/meta-analyses overall negative; no evidence for treating or improving prognosis of general AP	Rong et al[58]; Han et al[59]; Cao et al[60]; Pekgöz[61]
Tier 3-A: Animal therapeutic evidence multiple models	Butyrate/tributyrin	SCFAs (“supplementation and delivery optimization of butyrate and its derivatives”)	Animal therapeutic multiple models + ongoing trial	Rapid oral absorption, short half-life; phase II RCT (NCT06147635) ongoing, no results yet	Xia et al[133]; Zhao et al[134]; NIH[135]
	SPMs supplementation	Lipid mediators/SPMs (“SPM supplementation and optimization of delivery”)	Animal therapeutic multiple models	Native SPMs: Minute-scale half-life and poor targeting after systemic delivery (central bottleneck)	Liu et al[19]; Lu et al[27]
	ABT-702	Adenosine-signaling enhancement (“strategies to enhance adenosine signaling”)	Animal therapeutic multiple models (consistent in vitro and in vivo SAP)	No human AP data	Sun et al[57]
	MCC950	NLRP3 inhibition (“P2X7 receptor antagonism and NLRP3 inflammasome blockade”)	Animal therapeutic multiple models	No human AP data	Shen et al[52]; Gao et al[53]
	1-Methylspermidine	Polyamine metabolism (“targeted intervention strategies for polyamine metabolism”)	Animal therapeutic multiple models	Highly model-/phase-dependent; benefit confined to pancreas/early phase; renal accumulation and higher mortality at high doses	Hyvönen et al[100]
	FXR agonist	Bile acid signaling (“targeting FXR and TGR5”)	Animal therapeutic multiple models	OCA: Hepatotoxicity and other adverse effects; Gut-selective fexaramine safer but unvalidated in AP	Zhu et al[145]; Zheng et al[151]; Zhang et al[152]
	LXA4	LXA4 pathway (“targeting the LXA4 pathway and modulating pro-inflammatory mediators”)	Animal therapeutic multiple models	No human AP data	Yu et al[32]; Fu et al[33]; Shi et al[34]
	LY293111	LTB4/BLT1 axis (“targeting the LXA4 pathway and modulating pro-inflammatory mediators”)	Animal therapeutic multiple models	No human AP data	Li et al[36]
	KMO inhibitors	Downstream kynurenine pathway (“inhibition of the KMO pathway”)	Animal therapeutic multiple models (improved survival in some models)	No KMO-inhibition clinical trial in AP patients yet	Mole et al[66]; Hayes et al[73]
	Selenium supplementation	GPX4/GPX1 upregulation (“anti-ferroptotic metabolic intervention”)	Animal therapeutic multiple models	Clinically applicable dose and safety window undetermined	Han et al[117]; Swetha et al[118]
	iNOS inhibitors	Arginine-NO axis (“targeting the arginine-NO metabolic axis”)	Animal therapeutic multiple models	Benefits inconsistent across models; no population evidence	Shields et al[92]; Nishino et al[93]
	A2A receptor agonists	Adenosine pathway (“strategies to enhance adenosine signaling”)	Animal therapeutic multiple models	Potential risk of aggravating edema; no population evidence	Celiński et al[55]; Satoh et al[56]
	Emodin	P2X7/Nrf2/NF-κB multi-target [“emodin (a natural P2X7 antagonist and modulator of multiple metabolic pathways)”, “anti-ferroptotic metabolic intervention”]	Animal therapeutic multiple models	Low oral bioavailability; reported hepatic/renal toxicity; insufficient independent validation	Dong et al[62]; Hui et al[63]; Xu et al[64]; Shen et al[119]; Liu et al[120]; Dong et al[121]
	Baicalein	Multi-target [“multi-target natural products (baicalein as an example)”]	Animal therapeutic multiple models	Complex structure activity relationship; low oral bioavailability	Kuhnert et al[38]; Wang et al[39]; Dai et al[40]
	Lactate-metabolism modulation	Lactate/Lactylation (see “lactate metabolism and protein lactylation”)	Animal therapeutic multiple models (bidirectional effect)	Phase-/context-dependent bidirectional effect; modification sites and human relevance unclear	Jiang et al[125]; Han et al[126]
Tier 3-B: Animal therapeutic evidence single model	5-HTP	5-HT pathway (“modulation of the 5-HT pathway”)	Animal therapeutic single model	Single-model evidence; no human data	Wang et al[76]
	4-OI	Nrf2/ARE activation (“activation of the Nrf2-antioxidant response elements pathway”)	Animal therapeutic single model	No clinical translational data in AP	Mills et al[122]; Song et al[123]; Lu et al[124]
	ILA	Indole metabolites (“translational potential and limitations of indole-targeted therapies”)	Animal therapeutic single model	Limited bioavailability and transient effect; hard to maintain stable intraluminal ligand levels	Li et al[140]
	INT-777	TGR5 pathway (“targeting FXR and TGR5”)	Animal therapeutic single model	TGR5 may promote acinar injury; needs immune-cell selective activation/delivery	Li et al[155]
	P2X7 receptor antagonists	eATP-P2X7-NLRP3 axis (“P2X7 receptor antagonism and NLRP3 inflammasome blockade”)	Animal therapeutic single model	Human-murine P2X7 pharmacological differences; needs human-P2X7 selective compounds	Zhang et al[49]; Hoque et al[50]; Fujiwara et al[51]
	Selective mPGES-1 inhibitors	Selective PGE2 inhibition (“targeting the LXA4 pathway and modulating pro-inflammatory mediators”)	Animal therapeutic single model	Limited direct efficacy data in AP	Steinmetz-Späh and Jakobsson[35]
	Resistant starch/inulin (prebiotics)	Microbiota-SCFA (“supplementation and delivery optimization of butyrate and its derivatives”)	Animal therapeutic single model	No human AP data	Baxter et al[137]; Li et al[138]
	Blautia coccoides	Microbiota-bile acid axis (“targeting the gut microbiota-bile acid metabolic axis”)	Animal therapeutic single model	Single-model evidence; live-bacteria safety caution (PROPATRIA)4	Fu et al[158]; Nista et al[159]
	Spermidine (exogenous)	Polyamine metabolism (“targeted intervention strategies for polyamine metabolism”)	Animal therapeutic single model (plus network-pharmacology prediction)	Mostly network-pharmacology prediction/early validation; dose response and safety window undetermined	Shen et al[101]
	GV-971	Microbiota remodeling–enhanced butyrate production (“supplementation and delivery optimization of butyrate and its derivatives”)	Animal therapeutic single model	Single AP study; original indication controversial; reliability/reproducibility need independent validation	Chen et al[139]
Tier 4: Mechanistic extrapolation/no AP model	Nicotinamide riboside	NAD+ precursor supplementation (“NAD+ supplementation”)	Mechanistic extrapolation; no AP model	Combination with PARP inhibitor still conceptual; no direct validation in AP models	Conze et al[79]
	Citrulline (exogenous)	Arginine-NO axis (“targeting the arginine-NO metabolic axis”)	Mechanistic extrapolation (sepsis models) + AP biomarker; no AP model	Evidence from sepsis models and AP biomarker only; no AP efficacy model	Uyanga et al[94]; Chen et al[95]; Goswami et al[96]
	Dapansutrile	NLRP3 inhibition (“P2X7 receptor antagonism and NLRP3 inflammasome blockade”)	Safety from another indication (gout, phase II) + mechanistic extrapolation; no AP model	No direct efficacy data in AP	Li et al[54]
	Colonization with indole-producing probiotics	AhR-IL-22-intestinal barrier (“translational potential and limitations of indole-targeted therapies”)	Mechanistic extrapolation (evidence mainly from IBD models); no AP model	Validated only in IBD models; unconfirmed in AP models	Cui et al[141]; Li et al[142]
Appendix: Negative/cautionary evidence	SAMe	GSH system (“reconstitution of the GSH system”)	Animal negative/cautionary	Alone fails to restore pancreatic GSH, may worsen blockade and inflammation	Anstee and Day[113]; Rius-Pérez et al[114]
	MDL 72527	Inhibition of oxidative polyamine degradation (“targeted intervention strategies for polyamine metabolism”)	Animal negative	Monotherapy did not improve histological injury; blocking degradation by-products alone cannot reverse injury	Alhonen et al[102]; Mandal et al[103]; Räsänen et al[104]

¹Tiers represent an integrated ranking of translational readiness/directness of evidence rather than strength of efficacy in acute pancreatitis alone. Tier 2 ranks above Tier 3 because available human data (prophylaxis or safety from other indications) and an established safety profile bring it closer to clinical trials not because its efficacy evidence for treating established acute pancreatitis is stronger than that of Tier 3.

²The “evidence nature and context” column distinguishes the different evidence types: Human therapeutic (established acute pancreatitis); Human prophylaxis (e.g., post-endoscopic retrograde cholangiopancreatography, biliary); Animal therapeutic multiple models; Animal therapeutic single model; Safety extrapolation from other indications; and mechanistic extrapolation. Three boundaries must be strictly kept apart prophylactic evidence not equal to therapeutic evidence (e.g., N-acetylcysteine, ursodeoxycholic acid); efficacy in animals not equal to efficacy in humans; and approval/safety in other indications not equal to efficacy in acute pancreatitis.

³Tier definitions: Tier 1: Human therapeutic evidence for established acute pancreatitis (randomized controlled trial/meta-analysis/prospective or retrospective cohort); excludes prophylactic or other-indication data. Tier 2: Human data available but limited to prophylaxis, safety from other indications, or ongoing trials (not treatment of established acute pancreatitis), combined with animal therapeutic evidence; therapeutic evidence for established acute pancreatitis remains animal-only. Tier 3A: Animal therapeutic evidence only (post-onset administration), consistent across multiple models, with no human therapeutic data in acute pancreatitis. Tier 3B: Animal therapeutic evidence only (post-onset administration), a single model, with no human therapeutic data in acute pancreatitis. Tier 4: No acute pancreatitis model; evidence derives from models of other diseases (e.g., sepsis, inflammatory bowel disease), safety in other indications, or purely mechanistic extrapolation.

⁴Safety warning for microbiota-based interventions: The largest trial to date, PROPATRIA (296 patients with predicted severe acute pancreatitis), showed that multi-strain probiotic prophylaxis did not reduce infectious complications and significantly increased mortality; several guidelines accordingly do not recommend routine use.

UDCA: Ursodeoxycholic acid; TUDCA: Tauroursodeoxycholic acid; NAC: N-acetylcysteine; AP: Acute pancreatitis; SPMs: Specialized pro-resolving mediators; FXR: Farnesoid X receptor; LXA4: Lipoxin A4; KMO: Kynurenine-3-monooxygenase; iNOS: Inducible nitric oxide synthase; 5-HTP: 5-Hydroxytryptophan; 4-OI: 4-octyl itaconate; ILA: Indole-3-lactic acid; P2X7: P2X purinoceptor 7; mPGES: Membrane-associated prostaglandin E synthase; SAMe: S-adenosylmethionine; NAD⁺: Nicotinamide adenine dinucleotide; 5-HT: 5-hydroxytryptamine; SCFA: Short-chain fatty acid; GSH: Glutathione; GPX4: Glutathione peroxidase 4; XO: Xanthine oxidase; ROS: Reactive oxygen species; NLRP3: NOD-like receptor thermal protein domain associated protein 3; TGR5: Takeda G protein-coupled receptor 5; eATP: Extracellular adenosine triphosphate; PGE2: Prostaglandin E2; AhR: Aryl hydrocarbon receptor; IL: Interleukin; NO: Nitric oxide; PAR: Poly-adenosine diphosphate ribose; RCT: Randomized controlled trial; PBC: Primary biliary cirrhosis; ERCP: Endoscopic retrograde cholangiopancreatography; SAP: Severe acute pancreatitis; IBD: Inflammatory bowel disease; OCA: Obeticholic acid; PARP: Poly-adenosine diphosphate ribose polymerase.