Preconditioning with sufentanil confers protective effects in transplantation by attenuating hepatic ischemia-reperfusion injury

Table 1 Key molecular pathways of ferroptosis on hepatic ischemia-reperfusion injury

Regulatory pathway/factor	Mechanism in HIRI
TRPM2	Calcium-calcium overload (increase); ALOX12-dependent lipid peroxidation
IDO-1 (macrophage)	Immune activation
STAT1	miR-497-5p transcription (decrease)-HDAC7 activation
Pro-ferroptotic genes (Hmox1, Tfrc, Slc11a2)	Upregulation
Anti-ferroptotic genes (Slc40a1, Gpx4)	Downregulation
STAT3-HO-1/COX-2 axis	Regulation of iron metabolism and inflammation
JAK2/STAT3 pathway	Release of pro-inflammatory cytokines
MEK/ERK signaling pathway	Regulation of inflammatory response

HIRI: Hepatic ischemia-reperfusion injury; TRPM2: Transient receptor potential melastatin 2; IDO-1: Indoleamine 2, 3-dioxygenase 1; STAT1: Signal transducer and activator of transcription 1; STAT3: Signal transducer and activator of transcription 3; HO-1: Heme oxygenase 1; ALOX12: Arachidonate 12-lipoxygenase; HDAC7: Histone deacetylase 7; COX-2: Cyclooxygenase-2; JAK2: Janus kinase 2; MEK: Mitogen extracellular kinase; ERK: Extracellular signal-regulated kinase.

Table 2 Available data on strategies targeting hepatic ischemia-reperfusion injury

Strategy/drug	Animal evidence	Human evidence	Reported effect
Melatonin	Extensive	Limited	Positive
N-acetylcysteine	Extensive	Moderate	Mixed
Nobel gases	Limited	Limited	Insufficient
Caspase inhibitors	Extensive	Limited	Positive
P-selectin antagonists	Moderate	Limited	Mixed
Prostaglandins	Extensive	Moderate	Positive
Remifentanil	Moderate	Limited	Positive
Noble gases	Limited	Limited	insufficient
Akt activators	Moderate	None	Positive
PPARγ agonists	Moderate	None	Positive
miRNA based therapies	Moderate	None	Positive
Stem cell therapies	Extensive	Limited	Positive
Ischemic preconditioning	Expensive	Moderate	Positive
Ischemic postconditioning	Moderate	Limited	Mixed
Machine perfusion techniques	Extensive	Extensive	Positive

Akt: Activation of protein kinase B; PPARγ: Peroxisome proliferator-activated receptor gamma; miRNA: MicroRNA.

Table 3 Cytoprotective effects of sufentanil in ischemia-reperfusion injury across different organs

Organ	Main protective mechanisms	Biological outcomes
Myocardium	miR-125a/DRAM2 axis; activation of ERK1/2 pathway; activation of PI3K/Akt-GSK-3β pathway; modulation of Bax and Bcl-2 expression	Regulation of cardiomyocyte autophagy and oxidative injury; reduction of apoptosis
Kidney	Upregulation of miR-145-mediated autophagy; inhibition of KCNQ1OT1 and HMGB1 expression, promotion of miR-211-5p expression; activation of the PI3K/Akt/FOXO1	Regulation of autophagy; alleviation of inflammatory infiltration; suppress of cell apoptosis and oxidative stress
Brain	Activation of the Akt/GSK-3β pathway	Suppression of oxidative stress-related inflammation and ferroptosis
Liver	Suppression of the p38/ERK/JNK/NF-κB-p65/COX-2 pathways; upregulation of ATF3 expression; HIF-1α/KCNQ1OT1 axis; inhibition of ATF4-Induced TP53BP2 expression	Regulation of inflammatory response; mitigation of ferroptosis; reduction of apoptosis

DRAM2: Damage-regulated autophagy modulator protein 2; ERK: Extracellular signal-regulated kinase; PI3K: Phosphoinositide-3 kinase; Akt: Activation of protein kinase B; GSK-3β: Glycogen synthase kinase-3 beta; JNK: C-Jun N-terminal kinase; NF-κB-p65: Nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit; COX-2: Cyclooxygenase-2; ATF3: Activating transcription factor 3; HIF-1α: Hypoxia-inducible factor 1-alpha; ATF4: Activating transcription factor 4.

Table 4 Molecular mechanisms underlying the protective effects of sufentanil in hepatic ischemia-reperfusion injury

Signaling pathway	Sufentanil effect	Downstream mechanism	Consequences
p38/ERK/JNK/NF-κB-p65/COX-2	Inhibition	Suppression of inflammatory signaling	Cytokines production (decrease)
ATF4/TP53BP2 axis	Downregulation	Reduction of apoptosis	Hepatoprotection
ATF3 pathway	Restoration of ATF3 expression	GPX4 (increase), iron accumulation (decrease)	Attenuation of ferroptosis
HIF-1α/KCNQ1OT1 axis	Reduction of HIF-1α transcriptional activity	KCNQ1OT1 expression (decrease)	Inhibition of ferroptosis
KCNQ1OT1/SRSF1/ACSL4 pathway	ACSL4 levels stabilization	Limitation of PUFA oxidation	Inhibition of ferroptosis

ERK: Extracellular signal-regulated kinase; JNK: C-Jun N-terminal kinase; NF-κB-p65: Nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit; COX-2: Cyclooxygenase-2; ATF3: Activating transcription factor 3; HIF-1α: Hypoxia-inducible factor 1-alpha; ATF4: Activating transcription factor 4; SRSF1: Serine/arginine splicing factor 1; ACSL4: Acyl-CoA synthetase long-chain family member 4; GPX4: Glutathione peroxidase 4; PUFA: Polyunsaturated fatty acids.