. 2024 Nov 17;12(11):2627. doi: 10.3390/biomedicines12112627

Table 4.

Systematic summary of the molecular mechanisms involved in the pathogenesis of acute pancreatitis, their biological implications, and the derived potential targeted therapeutic interventions [63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106].

Mechanisms	Main Components	Key Players	Detailed Process	Consequences	Interactions	Potential Interventions
1. Premature Enzyme Activation [67,68,69,70]	Trypsinogen Autoactivation [67]	- Cationic trypsinogen (PRSS1) - Anionic trypsinogen (PRSS2) - Trypsin	- pH drop in acinar cells - Conformational change in trypsinogen - Autocatalytic cleavage of trypsinogen activation peptide - Formation of active trypsin	- Initiates zymogen activation cascade - Damages cellular structures - Triggers inflammatory responses	- Amplifies calcium signaling disruption - Activates NF-κB pathway - Induces acinar cell injury	- Trypsin-specific inhibitors - pH modulators - Trypsinogen stabilizers
	Cathepsin B-Mediated Activation [68]	- Cathepsin B - Trypsinogen - Lysosomal membrane proteins	- Lysosomal membrane permeabilization - Release of cathepsin B into cytosol - Cathepsin B cleaves trypsinogen activation peptide - Formation of active trypsin	- Accelerates trypsinogen activation - Contributes to lysosomal dysfunction - Enhances cellular damage	- Interacts with autophagy pathways - Contributes to oxidative stress - Amplifies inflammatory cascade	- Cathepsin B inhibitors (e.g., CA-074Me) - Lysosomal membrane stabilizers - Autophagy modulators
	Impaired Protective Mechanisms [69]	- SPINK1 - CTRC - α1-antitrypsin	- Overwhelmed SPINK1 capacity - Reduced CTRC-mediated trypsin degradation - Insufficient α1-antitrypsin levels	- Unchecked trypsin activity - Prolonged enzyme activation - Extended tissue damage	- Affects ER stress responses - Modulates inflammatory intensity - Influences cell death pathways	- SPINK1 analogues - CTRC activators - Recombinant α1-antitrypsin therapy
	Zymogen Co-localization [70]	- Zymogen granules -Lysosomes - Vacuoles	- Formation of large vacuoles - Fusion of zymogen granules with lysosomes - Creation of environment for enzyme activation	- Facilitates enzyme activation - Disrupts normal cellular architecture - Contributes to organelle dysfunction	- Linked to autophagy impairment - Affects intracellular trafficking - Contributes to ER stress	- Vacuole formation inhibitors - Intracellular trafficking modulators - Organelle stabilizers
2. Calcium Signaling Disruption [71,72,73,74]	Excessive Ca²⁺ Release from ER [71]	- IP3 receptors - Ryanodine receptors - SERCA pumps	- Increased IP3 production - IP3R activation and Ca²⁺ release - Ca²⁺-induced Ca²⁺ release via RyRs - Impaired SERCA function due to ATP depletion	- Sustained cytosolic Ca²⁺ elevation - ER Ca²⁺ store depletion - Mitochondrial Ca²⁺ overload	- Triggers ER stress - Exacerbates mitochondrial dysfunction - Activates Ca²⁺-dependent enzymes	- IP3R inhibitors (e.g., 2-APB) - RyR modulators - SERCA activators
	Enhanced Ca²⁺ Influx (SOCE) [72]	- STIM1 - Orai1 - TRPC channels	- ER Ca²⁺ depletion sensed by STIM1 - STIM1 oligomerization and translocation - Activation of Orai1 channels - Ca²⁺ influx from extracellular space	- Prolonged cytosolic Ca²⁺ elevation - Cellular energy depletion - Activation of Ca²⁺-dependent pathways	- Amplifies initial Ca²⁺ signaling disruption - Contributes to oxidative stress - Affects membrane potential	- SOCE inhibitors (e.g., GSK-7975A) - STIM1/Orai1 modulators - TRPC channel blockers
	Impaired Ca²⁺ Extrusion [73]	- PMCA pumps - Na+/Ca²⁺ exchangers - ATP	- ATP depletion impairs PMCA function - Reduced Na⁺/Ca²⁺ exchanger activity - Accumulation of cytosolic Ca²⁺	- Prolonged cytosolic Ca²⁺ elevation - Disruption of Ca²⁺ gradients - Cellular stress and dysfunction	- Exacerbates energy crisis - Contributes to oxidative stress - Affects membrane integrity	- PMCA activators - Na⁺/Ca²⁺ exchanger modulators - ATP supplementation strategies
	Mitochondrial Ca²⁺ Overload [74]	- Mitochondrial Ca²⁺ uniporter (MCU) - MPTP - Cyclophilin D	- Excessive Ca²⁺ uptake by MCU - Mitochondrial Ca²⁺ overload - MPTP opening - Mitochondrial swelling and dysfunction	- Impaired ATP production - Increased ROS generation - Cytochrome c release	- Central to mitochondrial dysfunction - Contributes to apoptosis initiation - Affects cellular energy status	- MCU inhibitors - MPTP inhibitors (e.g., cyclosporin A) - Mitochondrial Ca²⁺ buffering enhancers
3. Mitochondrial Dysfunction [75,76,77,78]	MPTP Opening [75]	- Cyclophilin D - ATP synthase - Voltage-dependent anion channel (VDAC)	- Ca²⁺ overload and oxidative stress trigger MPTP opening - Loss of mitochondrial membrane potential - Swelling of mitochondria - Release of proapoptotic factors	- Energy crisis - Increased ROS production - Initiation of cell death pathways	- Central to mitochondria-mediated apoptosis - Exacerbates oxidative stress - Affects Ca²⁺ homeostasis	- Cyclophilin D inhibitors - MPTP stabilizers - Mitochondrial membrane potential preservers
	ATP Depletion [76]	- Electron transport chain complexes - ATP synthase - ADP/ATP translocase	- Impaired electron transport - Reduced proton gradient - Decreased ATP synthesis - Impaired ATP export from mitochondria	- Cellular energy crisis - Impaired ion pump function - Disruption of cellular processes	- Affects all ATP-dependent processes - Exacerbates Ca²⁺ overload - Impairs cellular repair mechanisms	- ETC complex activators - ATP synthase modulators - Mitochondrial substrate supplementation
	ROS Overproduction [77]	- Complex I and III of ETC - Superoxide dismutase (SOD) - Glutathione peroxidase	- Electron leakage from ETC - Formation of superoxide radicals - Overwhelmed antioxidant defenses - Oxidative damage to mitochondrial components	- Oxidative damage to proteins, lipids, and DNA - Further impairment of mitochondrial function - Activation of stress response pathways	- Contributes to MPTP opening - Activates inflammatory pathways - Enhances ER stress	- Mitochondria-targeted antioxidants (e.g., MitoQ) - SOD mimetics - ETC electron leak inhibitors
	Cytochrome c Release [78]	- Bax/Bak - Bcl-2 - Cytochrome c - Apaf-1	- Proapoptotic Bax/Bak activation - Outer mitochondrial membrane permeabilization - Cytochrome c release into cytosol - Formation of apoptosome	- Initiation of intrinsic apoptosis pathway - Caspase activation - Propagation of cell death signals	- Central to apoptosis regulation - Influences inflammatory responses - Affects overall cell fate decisions	- Bcl-2 inhibitors/activators - Caspase inhibitors - Apoptosome formation inhibitors
4. Endoplasmic Reticulum (ER) Stress [79,80,81,82]	Unfolded Protein Response (UPR) Activation [79]	- BiP/GRP78 - PERK - IRE1α - ATF6	- Accumulation of misfolded proteins - BiP dissociation from ER stress sensors - Activation of PERK, IRE1α, and ATF6 pathways - Induction of UPR target genes	- Global protein synthesis attenuation - Upregulation of chaperones - Enhanced ER-associated degradation (ERAD)	- Modulates inflammatory responses - Influences autophagy regulation - Affects cell survival decisions	- Chemical chaperones (e.g., 4-PBA, TUDCA) - UPR modulators - Protein folding enhancers
	PERK Pathway [80]	- PERK - eIF2α - ATF4 - CHOP	- PERK dimerization and autophosphorylation - eIF2α phosphorylation - Selective translation of ATF4 - Induction of CHOP	- Global protein synthesis inhibition - Upregulation of stress response genes - Potential apoptosis induction via CHOP	- Affects cellular redox state - Modulates autophagy - Influences lipid metabolism	- PERK inhibitors - eIF2α dephosphorylation modulators - CHOP inhibitors
	IRE1α Pathway [81]	- IRE1α - XBP1 - TRAF2 - JNK	- IRE1α oligomerization and activation - XBP1 mRNA splicing - JNK activation via TRAF2 - Regulated IRE1-dependent decay (RIDD)	- Upregulation of ER chaperones and ERAD components - Activation of inflammatory pathways - Selective mRNA degradation	- Crosstalk with inflammatory signaling - Affects lipid metabolism - Modulates cell death pathways	- IRE1α RNase inhibitors - JNK inhibitors - XBP1 modulators
	ATF6 Pathway [82]	- ATF6 - S1P and S2P proteases - ERAD components	- ATF6 translocation to Golgi - Cleavage by S1P and S2P - Nuclear translocation of cleaved ATF6 - Transcription of UPR target genes	- Increased ER folding capacity - Enhanced ERAD - Expansion of ER membrane	- Affects lipid biosynthesis - Modulates inflammatory responses - Influences cellular adaptation to stress	- ATF6 activators/inhibitors - S1P/S2P modulators - ERAD enhancers
5. Autophagy Impairment [83,84,85,86]	Initiation Defects [83]	- ULK1 complex - mTORC1 - AMPK	- Dysregulation of mTORC1/AMPK signaling - Impaired ULK1 complex activation - Reduced autophagosome formation initiation	- Accumulation of cellular debris - Impaired stress response - Reduced cellular quality control	- Affects cellular energy sensing - Influences ER stress responses - Modulates inflammatory pathways	- mTOR inhibitors (e.g., rapamycin) - AMPK activators - ULK1 activators
	Autophagosome Formation Defects [84]	- Beclin-1/VPS34 complex - ATG proteins (e.g., ATG5, ATG7) - LC3	- Impaired nucleation of phagophore - Defective elongation of autophagosomal membrane - Reduced LC3 lipidation	- Inefficient sequestration of cargo - Accumulation of protein aggregates and damaged organelles - Cellular stress amplification	- Affects mitochondrial quality control - Influences ER stress resolution - Modulates inflammatory responses	- Beclin-1/VPS34 activators - ATG protein modulators - LC3 lipidation enhancers
	Lysosomal Dysfunction [85]	- v-ATPase - Lysosomal hydrolases - LAMP proteins	- Impaired lysosomal acidification - Reduced hydrolase activity - Defective lysosomal membrane integrity	- Accumulation of autophagosomes - Inefficient degradation of cellular components - Potential release of lysosomal contents	- Exacerbates ER stress - Contributes to inflammatory activation - Affects cellular metabolism	- v-ATPase activators - Lysosomal membrane stabilizers - Hydrolase replacement therapies
	Autophagosome–Lysosome Fusion Defects [86]	- SNARE proteins - Rab7 - HOPS complex	- Impaired tethering of autophagosomes to lysosomes - Defective SNARE complex formation - Reduced fusion efficiency	- Accumulation of autophagosomes - Inefficient completion of autophagic flux - Cellular stress due to incomplete degradation	- Affects vesicular trafficking - Influences protein and organelle turnover - Modulates cellular homeostasis	- Rab7 activators - SNARE complex modulators - HOPS complex enhancers
6. Inflammatory Response [87,88,89,90]	DAMPs Release [87]	- HMGB1 - ATP - DNA - Heat shock proteins	- Cellular damage/necrosis - Release of intracellular components - Recognition by pattern recognition receptors (PRRs)	- Activation of innate immune responses - Initiation of sterile inflammation - Amplification of tissue damage	- Triggers TLR signaling - Activates NLRP3 inflammasome - Promotes neutrophil extracellular traps (NETs)	- DAMP neutralizing antibodies - TLR antagonists - HMGB1 inhibitors
	TLR Activation [88]	- TLR2, TLR4, TLR9 - MyD88 - TRIF	- DAMP recognition by TLRs - Recruitment of adaptor proteins - Activation of downstream signaling cascades	- NF-κB and AP-1 activation - Proinflammatory cytokine production - Leukocyte recruitment	- Amplifies inflammatory signaling - Influences cell death decisions - Modulates adaptive immune responses	- TLR antagonists - MyD88 inhibitors - NF-κB pathway modulators
	Inflammasome Activation [89]	- NLRP3 - ASC - Caspase-1 - IL-1β, IL-18	- Priming step: NF-κB-mediated upregulation of NLRP3 and pro-IL-1β - Activation step: NLRP3 oligomerization and inflammasome assembly - Caspase-1 activation and cytokine processing	- Release of mature IL-1β and IL-18 - Pyroptosis induction - Amplification of inflammatory responses	- Crosstalk with TLR signaling - Influences neutrophil recruitment - Affects adaptive immunity	- NLRP3 inhibitors - Caspase-1 inhibitors - IL-1 receptor antagonists
	Neutrophil Infiltration [90]	- Chemokines (e.g., IL-8) - Adhesion molecules - Neutrophil granule proteins	- Chemokine-guided migration - Adhesion to endothelium - Transmigration into tissue - Release of inflammatory mediators and NETs	- Tissue damage via proteases and ROS - Amplification of inflammatory signals - Potential microvascular occlusion	- Contributes to oxidative stress - Enhances vascular permeability - Modulates adaptive immune responses	- Chemokine receptor antagonists - Adhesion molecule inhibitors - NET inhibitors
7. Cell Death [91,92,93,94]	Apoptosis [91]	- Caspases (8, 9, 3, 7) - Bcl-2 family proteins - Cytochrome c - Apaf-1	- Extrinsic pathway: death receptor activation - Intrinsic pathway: mitochondrial outer membrane permeabilization - Caspase cascade activation - Controlled cellular dismantling	- Controlled cell death without inflammation - Maintenance of membrane integrity - Efficient clearance by phagocytes	- Influenced by ER stress and mitochondrial dysfunction - Modulates inflammatory responses - Affects tissue repair processes	- Caspase inhibitors - Bcl-2 family modulators - Death receptor antagonists
	Necrosis [92]	- RIPK1, RIPK3 - MLKL - Cyclophilin D	- Cellular stress or damage beyond repair capacity - ATP depletion and ion pump failure - Cellular swelling and membrane rupture - Release of cellular contents	- Uncontrolled cell death with inflammation - Release of DAMPs - Tissue architecture disruption	- Exacerbates inflammatory responses - Triggers adaptive immune activation - Affects surrounding healthy tissue	- Necrosis inhibitors - Cellular energy preservers - Membrane stabilizers
	Necroptosis [93]	- RIPK1, RIPK3 - MLKL - FADD, caspase-8	- Death receptor activation in absence of caspase-8 activity - RIPK1-RIPK3 necrosome formation - MLKL phosphorylation and oligomerization - Membrane permeabilization	- Programmed necrotic cell death - Inflammatory response induction - Potential pathogen clearance	- Crosstalk with apoptosis pathways - Modulates inflammatory signaling - Influences tissue damage extent	- RIPK1 inhibitors (e.g., Necrostatin-1) - RIPK3 inhibitors - MLKL inhibitors
	Pyroptosis [94]	- Caspase-1, Caspase-11 - Gasdermin D - NLRP3 inflammasome	- Inflammasome activation - Caspase-1/11 activation - Gasdermin D cleavage and pore formation - Cell lysis and IL-1β/IL-18 release	- Inflammatory form of programmed cell death - Cytokine release and inflammation amplification - Potential pathogen clearance	- Closely linked to inflammasome activation - Amplifies inflammatory responses - Affects tissue integrity	- Caspase-1 inhibitors - Gasdermin D inhibitors - IL-1 receptor antagonists
8. Oxidative and Nitrosative Stress [95,96,97,98]	Mitochondrial ROS Production [95]	- Complexes I and III of ETC - Superoxide dismutase (SOD) - Glutathione peroxidase	- Electron leakage from ETC - Superoxide radical formation - Conversion to H₂O₂ by SOD - Detoxification by glutathione system	- Oxidative damage to mitochondrial components - mtDNA mutations - Impaired ATP production	- Exacerbates mitochondrial dysfunction - Triggers MPTP opening - Activates stress response pathways	- Mitochondria-targeted antioxidants - ETC modulators - SOD mimetics
	NADPH Oxidase Activation [96]	- NOX enzymes - p47phox, p67phox - Rac proteins	- Assembly of NOX complex at membrane - Electron transfer to molecular oxygen - Superoxide production - Conversion to other ROS species	- Extracellular and phagosomal ROS production - Oxidative damage to cellular components - Activation of redox-sensitive pathways	- Contributes to neutrophil-mediated damage - Modulates inflammatory signaling - Affects vascular function	- NOX inhibitors - Assembly inhibitors - ROS scavengers
	Xanthine Oxidase Activation [97]	- Xanthine dehydrogenase - Xanthine oxidase - Hypoxanthine/xanthine	- Conversion of xanthine dehydrogenase to oxidase - Hypoxanthine/xanthine oxidation - Superoxide and H₂O₂ production - Uric acid formation	- Increased ROS during ischemia reperfusion - Oxidative damage to cellular components - Potential NLRP3 inflammasome activation	- Exacerbates ischemia-reperfusion injury - Contributes to vascular dysfunction - Modulates inflammatory responses	- Xanthine oxidase inhibitors (e.g., allopurinol) - Antioxidants - Uric acid lowering agents
	Nitrosative Stress [98]	- iNOS - Peroxynitrite - Nitrotyrosine	- iNOS upregulation and activation - Excessive NO production - Reaction with superoxide to form peroxynitrite - Protein tyrosine nitration	- Nitrosative modification of proteins - DNA and lipid damage - Mitochondrial dysfunction	- Interacts with oxidative stress pathways - Modulates cellular signaling - Affects enzyme function and protein stability	- iNOS inhibitors - Peroxynitrite scavengers - Protein denitration strategies
9. Microcirculatory Dysfunction [99,100,101,102]	Vasoconstriction [99]	- Endothelin-1 - Thromboxane A2 - Angiotensin II	- Release of vasoconstrictors - Smooth muscle contraction - Reduced vessel diameter - Decreased blood flow	- Tissue ischemia - Impaired nutrient and oxygen delivery - Exacerbation of cellular stress	- Contributes to oxidative stress - Affects inflammatory cell recruitment - Modulates tissue edema	- Endothelin receptor antagonists - Thromboxane inhibitors - Vasodilators
	Increased Vascular Permeability [100]	- VEGF - Bradykinin - Histamine - Leukotrienes	- Release of permeability factors - Endothelial cell contraction - Tight junction disruption - Increased paracellular transport	- Tissue edema - Fluid sequestration - Potential compartment syndrome	- Exacerbates inflammatory responses - Affects drug delivery to tissue - Modulates immune cell extravasation	- VEGF inhibitors - Bradykinin receptor antagonists - Antihistamines
	Leukocyte–Endothelial Interactions [101]	- Selectins (P, E, L) - Integrins - ICAM-1, VCAM-1	- Leukocyte rolling (selectins) - Firm adhesion (integrins) - Transmigration - Release of inflammatory mediators	- Increased inflammatory cell infiltration - Endothelial activation and dysfunction - Microvascular occlusion	- Amplifies local inflammation - Contributes to tissue damage - Affects microvascular blood flow	- Selectin inhibitors - Integrin antagonists - Adhesion molecule blockers
	Microthrombi Formation [102]	- Tissue factor - Platelets - Fibrin - von Willebrand factor	- Tissue factor exposure - Platelet activation and aggregation - Fibrin deposition - Thrombus formation	- Microvascular occlusion - Tissue ischemia - Potential organ dysfunction	- Interacts with coagulation cascades - Affects inflammatory responses - Modulates tissue repair processes	- Anticoagulants - Antiplatelet agents - Fibrinolytic therapies
10. Genetics [103,104,105,106]	PRSS1 Mutations [103]	- Cationic trypsinogen - Trypsin	- Gain-of-function mutations in PRSS1 - Enhanced trypsinogen autoactivation - Resistance to protective mechanisms - Increased trypsin activity	- Increased susceptibility to pancreatitis - Enhanced acinar cell injury - Chronic inflammation and fibrosis	- Amplifies premature enzyme activation - Affects cellular stress responses - Modulates inflammatory pathways	- Personalized trypsin inhibitors - Gene therapy approaches - Pancreatic enzyme replacement
	SPINK1 Mutations [104]	- Pancreatic secretory trypsin inhibitor	- Loss-of-function mutations in SPINK1 - Reduced trypsin inhibition capacity - Imbalance in protease–antiprotease equilibrium - Enhanced trypsin activity	- Increased risk of pancreatitis - Exacerbation of acinar cell damage - Potential progression to chronic pancreatitis	- Interacts with trypsin activation pathways - Affects ER stress responses - Modulates inflammatory intensity	- SPINK1 supplementation strategies - Alternative protease inhibitors - Targeted anti-inflammatory approaches
	CFTR Mutations [105]	- Cystic fibrosis transmembrane conductance regulator	- Impaired CFTR function - Altered ductal secretion - Changes in pancreatic juice composition - Potential protein precipitation in ducts	- Increased risk of pancreatitis - Ductal obstruction - Potential progression to pancreatic insufficiency	- Affects fluid and bicarbonate secretion - Modulates acinar–ductal interactions - Influences inflammatory responses	- CFTR modulators/potentiators - Mucolytic therapies - Ductal function enhancers
	CTRC Mutations [106]	- Chymotrypsin C	- Loss-of-function mutations in CTRC - Impaired trypsin degradation - Prolonged trypsin activity - Enhanced risk of trypsin-mediated damage	- Increased susceptibility to pancreatitis - Exacerbation of acinar cell injury - Potential chronic inflammation	- Interacts with trypsin activation/inactivation pathways - Affects protease–antiprotease balance - Modulates cellular stress responses	- CTRC replacement strategies - Alternative trypsin degradation enhancers - Targeted protease inhibitors

ATP—adenosine triphosphate; ADP—adenosine diphosphate; ASC—apoptosis-associated speck-like protein containing a CARD; ATF4—activating transcription factor 4; ATF6—activating transcription factor 6; Bcl-2—B-cell lymphoma 2; BiP—binding immunoglobulin protein; CFTR—cystic fibrosis transmembrane conductance regulator; CHOP—C/EBP homologous protein; CINC—cytokine-induced neutrophil chemoattractant; CTRC—chymotrypsin C; DAMPs—damage-associated molecular patterns; DNA—deoxyribonucleic acid; ER—endoplasmic reticulum; ETC—electron transport chain; ERAD—ER-associated degradation; FADH—flavin adenine dinucleotide; GRP78—glucose-regulated protein 78; H₂O₂—hydrogen peroxide; HMGB1—high mobility group box 1; HOPS—homotypic fusion and protein sorting; ICAM-1—intercellular adhesion molecule 1; IL—interleukin; iNOS—inducible nitric oxide synthase; IP3R—inositol 1,4,5-trisphosphate receptor; IRE1α—inositol-requiring enzyme 1α; JNK—c-Jun N-terminal kinase; LAMP—lysosomal-associated membrane protein; LC3—microtubule-associated protein 1A/1B-light chain 3; MCU—mitochondrial calcium uniporter; MLKL—mixed lineage kinase domain-like protein; MPTP—mitochondrial permeability transition pore; mTORC1—mammalian target of papamycin complex 1; MyD88—myeloid differentiation primary response 88; NADPH—nicotinamide adenine dinucleotide phosphate; NETs—neutrophil extracellular traps; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3—NOD-, LRR-, and pyrin-domain-containing protein 3; NO—nitric oxide; NOX—NADPH oxidase; PERK—protein kinase R (PKR)-like endoplasmic reticulum kinase; PMCA—plasma membrane Ca²⁺ ATPase; PRRs—pattern recognition receptors; PRSS1—protease serine 1 (cationic trypsinogen); PSTI—pancreatic secretory trypsin inhibitor; RIPK—receptor-interacting serine/threonine-protein kinase; ROS—reactive oxygen species; RyR—ryanodine receptor; S1P—site-1 protease; S2P—site-2 protease; SERCA—sarco-/endoplasmic reticulum Ca2+-ATPase; SNARE—soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SOD—superoxide dismutase; SPINK1—serine protease inhibitor Kazal type 1; STIM1—stromal interaction molecule 1; TLR—toll-like receptor; TNF-α—tumor necrosis factor alpha; TRAF2—TNF receptor-associated factor 2; TRIF—TIR-domain-containing adapter-inducing interferon-β; ULK1—Unc-51-like autophagy-activating kinase 1; UPR—unfolded protein response; VCAM-1—vascular cell adhesion molecule 1; VEGF—vascular endothelial growth factor; VPS34—vacuolar protein sorting 34; XBP1—X-box binding protein 1.