Regenerative Roles of the Cyclooxygenase-2 Pathway in Neovascularization and Stem Cell Regulation: A Brief Perspective from In Vitro and In Vivo Studies
Main Article Content
Cyclooxygenase-2 (COX-2) is a key enzyme in prostanoid production and is best known as a mediator of the inflammatory response. Beyond this well-established role, COX-2 also contributes to tissue regeneration by promoting neovascularization and supporting stem cell recruitment, proliferation, and differentiation. Despite this, research on harnessing the COX-2 pathway as a therapeutic tool, rather than solely as a target for inhibition, remains limited, presenting a promising avenue for future studies. In this review, we summarize current insights from both in vitro and in vivo models into COX-2 signaling in tissue regeneration, focusing on molecular mechanisms through which its downstream mediators, especially prostaglandin (PGE2), regulate vascular formation, tissue growth, and stem cell function. We also briefly outline the dual nature of these processes, which can either facilitate repair or drive pathological outcomes, and discuss emerging strategies for achieving controlled therapeutic applications.
Keywords:
Tissue regeneration
Cyclooxygenase-2
1. Wang B, Wu L, Chen J, et al. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther.2021;6(1):94.
2. Ju Z, Li M, Xu J, et al. Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years. Acta Pharm Sin B. 2022;12(6):2790–2807.
3. Hosono K, Kojo K, Narumiya S, et al. Prostaglandin E receptor EP4 stimulates lymphangiogenesis to promote mucosal healing during DSS-induced colitis. Biomedicine & Pharmacotherapy. 2020;128:110264.
4. Zhang S, Liu Y, Zhang X, et al. Prostaglandin E2 hydrogel improves cutaneous wound healing via M2 macrophages polarization. Theranostics. 2018;8(19):5348–5361.
5. Liu X, Yu T, Tan X, et al. Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2. Elife. 2023;12.
6. Gao X, Usas A, Lu A, et al. Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms. Hum Mol Genet. 2016;25(15):3216–3231
7. Zheng C, Qu YX, Wang B, et al. COX-2/PGE2 facilitates fracture healing by activating the Wnt/β-catenin signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23(22):9721–9728.
8. Zhang Y, Wang J, Lv Z, et al. Cox-2 promotes mesenchymal stem cells differentiation into cardiocytes by activating JNK and ERK pathway. Biochem Biophys Res Commun. 2016;480(1):101–105.
9. Basile DP. Macrophage dynamics in kidney repair: elucidation of a COX-2–dependent MafB pathway to affect macrophage differentiation. Kidney Int. 2022;101(1):15–18.
10. Smith WL, Urade Y, Jakobsson P-J. Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis. Chem Rev. 2011;111(10):5821–5865.
11. Miciaccia M, Belviso BD, Iaselli M, et al. Three-dimensional structure of human cyclooxygenase (hCOX)-1. Sci Rep. 2021;11(1):4312.
12. Lucido MJ, Orlando BJ, Vecchio AJ, et al. Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry. Biochemistry. 2016;55(8):1226–1238.
13. Shieh J-M, Tsai Y-J, Ma M-C, et al. The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts. Sci Rep. 2024;14(1):7559.
14. Kang X, Qiu J, Li Q, et al. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Sci Rep. 2017;7(1):9459.
15. Zasłona Z, Pålsson-McDermott EM, Menon D, et al. The Induction of Pro–IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2 Production. The Journal of Immunology. 2017;198(9):3558–3564.
16. Zheng S-Q, Gong Z-Y, Lu C-D, et al. Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor α in a β-amyloid protein -dependent mechanism. Oncotarget. 2017;8(61):102801–102819.
17. Bonanno A, Albano GD, Siena L, et al. Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts. Prostaglandins Leukot Essent Fatty Acids. 2016;106:11–18.
18. Domingo C, Palomares O, Sandham DA, et al. The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation. Respir Res 2018;19(1):189; doi: 10.1186/s12931-018-0893-x.
19. Joo M, Sadikot RT. PGD Synthase and PGD2 in Immune Resposne. Mediators Inflamm. 2012;2012:1–6.
20. Szczuko M, Kozioł I, Kotlęga D, et al. The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review. Int J Mol Sci. 2021;22(21):11644.
21. Yuui K, Kudo R, Kasuda S. Arterial thromboxane A2-induced transient contraction after IL-1β exposure. Eur J Inflamm. 2022;20.
22. Dorris SL, Peebles RS. PGI2 as a Regulator of Inflammatory Diseases. Mediators Inflamm. 2012;2012:1–9.
23. Sugimoto Y, Narumiya S. Prostaglandin E Receptors. Journal of Biological Chemistry. 2007;282(16):11613–11617.
24. Yang C-M, Yang C-C, Hsiao L-D, et al. Upregulation of COX-2 and PGE2 Induced by TNF-α Mediated Through TNFR1/MitoROS/PKCα/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts. J Inflamm Res. 2021;Volume 14:2807–2824
25. Neuschäfer-Rube F, Schön T, Kahnt I, et al. LDL-Dependent Regulation of TNFα/PGE2 Induced COX-2/mPGES-1 Expression in Human Macrophage Cell Lines. Inflammation. 2023;46(3):893–911.
26. Ariasnegrete S, Keller K, Chadee K. Proinflammatory Cytokines Regulate Cyclooxygenase-2 mRNA Expression in Human Macrophages. Biochem Biophys Res Commun. 1995;208(2):582–589.
27. Chabane N, Zayed N, Martel-Pelletier J, et al. Interleukin-1-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in human OA chondrocytes is associated with histone H3K4 methylation. J Transl Med. 2010;8(S1):P59.
28. Liu W, Reinmuth N, Stoeltzing O, et al. Cyclooxygenase-2 Is Up-Regulated by Interleukin-1β in Human Colorectal Cancer Cells via Multiple Signaling Pathways1. Cancer Res. 2003;63(13):3632–3636.
29. Kirkby NS, Zaiss AK, Wright WR, et al. Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies. Biochem Biophys Res Commun. 2013;438(2):249–256.
30. Nagano S. Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines. Int Immunol. 2002;14(7):733–740.
31. Arfeen M, Dhaked DK, Mani V. Multipotent Effect of Clozapine on Lipopolysaccharide-Induced Acetylcholinesterase, Cyclooxygenase-2,5-Lipoxygenase, and Caspase-3: In Vivo and Molecular Modeling Studies. Molecules. 2025;30(2):266.
32. Muñoz M, Sánchez A, Pilar Martínez M, et al. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. Free Radic Biol Med. 2015;84:77–90.
33. Onodera Y, Teramura T, Takehara T, et al. Reactive oxygen species induce Cox‐2 expression via TAK1 activation in synovial fibroblast cells. FEBS Open Bio. 2015;5(1):492–501.
34. Kiritoshi S, Nishikawa T, Sonoda K, et al. Reactive Oxygen Species from Mitochondria Induce Cyclooxygenase-2 Gene Expression in Human Mesangial Cells. Diabetes. 2003;52(10):2570–2577.
35. Kage K, Fujita N, Oh-hara T, et al. Basic Fibroblast Growth Factor Induces Cyclooxygenase-2 Expression in Endothelial Cells Derived from Bone. Biochem Biophys Res Commun. 1999;254(1):259–263.
36. Tessner TG, Muhale F, Schloemann S, et al. Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;284(2):G269–G279.
37. Tamura M, Sebastian S, Gurates B, et al. Vascular Endothelial Growth Factor Up-Regulates Cyclooxygenase-2 Expression in Human Endothelial Cells. J Clin Endocrinol Metab. 2002;87(7):3504–3507.
38. Saha D, Datta PK, Sheng H, et al. Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells. Neoplasia. 1999;1(6):508–517.
39. Yang Y, Geng Y, Cheng X, et al. Cyclooxygenase 2 contributes to the hypoxia induced aggravation of the neuroinflammation response stimulated by lipopolysaccharide in microglia. Exp Ther Med. 2023;25(3):123.
40. Heikal L, Ferns G. Hypoxia, Angiogenesis and Atherogenesis. In: Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy InTech; 2017.
41. Zhang Y, Daaka Y. PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway. Blood. 2011;118(19):5355–5364.
42. Hosono K, Isonaka R, Kawakami T, et al. Signaling of Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice. PLoS One 2016;11(10):e0162532.
43. Blitek A, Szymanska M, Morawska-Pucinska E, et al. Prostacyclin receptor (PTGIR) in the porcine endometrium: Regulation of expression and role in luminal epithelial and stromal cells. Theriogenology. 2015;84(6):969–982.
44. Szymanska M, Blitek A. Diverse effects of prostacyclin on angiogenesis-related processes in the porcine endometrium. Sci Rep. 2023;13(1):14133.
45. Ho AT V., Palla AR, Blake MR, et al. Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences. 2017;114(26):6675–6684.
46. Wang YX, Palla AR, Ho ATV, et al. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Cell Stem Cell. 2025;32(7):1154-1169.e9.
47. Correia MR, Han SW, Escalante T, et al. The role of the cyclooxygenase-2 pathway in tissue ischemia and revascularization following skeletal muscle injury induced by bothropic snake venom. Microvasc Res. 2025;157:104760.
48. Li J, Chen H, Xiong Q, et al. Celecoxib disrupts temporal coordination of TGF-β/α-SMA signaling in skeletal muscle repair: a time-dependent study of fibrosis and inflammation. Eur J Med Res. 2025;30(1):703.
49. Kim H-B, Kim M, Park Y-S, et al. Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice. Gastroenterology. 2017;152(3):616–630.
50. Huang M, Wang L, Chen J, et al. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. Int J Oncol. 2016;48(5):2144–2154.
51. Hashemi Goradel N, Najafi M, Salehi E, et al. Cyclooxygenase‐2 in cancer: A review. J Cell Physiol. 2019;234(5):5683–5699.
52. Huang H, Chen S, Cheng H, et al. The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model. J Nanobiotechnology. 2022;20(1):95.
53. Hugo HJ, Saunders C, Ramsay RG, et al. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis. J Mammary Gland Biol Neoplasia. 2015;20(3–4):109–119.
54. Yao C, Narumiya S. Prostaglandin‐cytokine crosstalk in chronic inflammation. Br J Pharmacol. 2019;176(3):337–354.
55. Chun K-S, Kim E-H, Kim D-H, et al. Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update. Biochem Pharmacol. 2024;228:116259.
56. Tang Q, Chen L-L, Wei F, et al. Effect of 15-Deoxy-[INCREMENT]12,14-prostaglandin J2 Nanocapsules on Inflammation and Bone Regeneration in a Rat Bone Defect Model. Chin Med J. 2017;130(3):347–356.
2. Ju Z, Li M, Xu J, et al. Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years. Acta Pharm Sin B. 2022;12(6):2790–2807.
3. Hosono K, Kojo K, Narumiya S, et al. Prostaglandin E receptor EP4 stimulates lymphangiogenesis to promote mucosal healing during DSS-induced colitis. Biomedicine & Pharmacotherapy. 2020;128:110264.
4. Zhang S, Liu Y, Zhang X, et al. Prostaglandin E2 hydrogel improves cutaneous wound healing via M2 macrophages polarization. Theranostics. 2018;8(19):5348–5361.
5. Liu X, Yu T, Tan X, et al. Renal interstitial cells promote nephron regeneration by secreting prostaglandin E2. Elife. 2023;12.
6. Gao X, Usas A, Lu A, et al. Cyclooxygenase-2 deficiency impairs muscle-derived stem cell-mediated bone regeneration via cellular autonomous and non-autonomous mechanisms. Hum Mol Genet. 2016;25(15):3216–3231
7. Zheng C, Qu YX, Wang B, et al. COX-2/PGE2 facilitates fracture healing by activating the Wnt/β-catenin signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23(22):9721–9728.
8. Zhang Y, Wang J, Lv Z, et al. Cox-2 promotes mesenchymal stem cells differentiation into cardiocytes by activating JNK and ERK pathway. Biochem Biophys Res Commun. 2016;480(1):101–105.
9. Basile DP. Macrophage dynamics in kidney repair: elucidation of a COX-2–dependent MafB pathway to affect macrophage differentiation. Kidney Int. 2022;101(1):15–18.
10. Smith WL, Urade Y, Jakobsson P-J. Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis. Chem Rev. 2011;111(10):5821–5865.
11. Miciaccia M, Belviso BD, Iaselli M, et al. Three-dimensional structure of human cyclooxygenase (hCOX)-1. Sci Rep. 2021;11(1):4312.
12. Lucido MJ, Orlando BJ, Vecchio AJ, et al. Crystal Structure of Aspirin-Acetylated Human Cyclooxygenase-2: Insight into the Formation of Products with Reversed Stereochemistry. Biochemistry. 2016;55(8):1226–1238.
13. Shieh J-M, Tsai Y-J, Ma M-C, et al. The cyclooxygenase-2 upregulation mediates production of PGE2 autacoid to positively regulate interleukin-6 secretion in chronic rhinosinusitis with nasal polyps and polyp-derived fibroblasts. Sci Rep. 2024;14(1):7559.
14. Kang X, Qiu J, Li Q, et al. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Sci Rep. 2017;7(1):9459.
15. Zasłona Z, Pålsson-McDermott EM, Menon D, et al. The Induction of Pro–IL-1β by Lipopolysaccharide Requires Endogenous Prostaglandin E2 Production. The Journal of Immunology. 2017;198(9):3558–3564.
16. Zheng S-Q, Gong Z-Y, Lu C-D, et al. Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor α in a β-amyloid protein -dependent mechanism. Oncotarget. 2017;8(61):102801–102819.
17. Bonanno A, Albano GD, Siena L, et al. Prostaglandin E2 possesses different potencies in inducing Vascular Endothelial Growth Factor and Interleukin-8 production in COPD human lung fibroblasts. Prostaglandins Leukot Essent Fatty Acids. 2016;106:11–18.
18. Domingo C, Palomares O, Sandham DA, et al. The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation. Respir Res 2018;19(1):189; doi: 10.1186/s12931-018-0893-x.
19. Joo M, Sadikot RT. PGD Synthase and PGD2 in Immune Resposne. Mediators Inflamm. 2012;2012:1–6.
20. Szczuko M, Kozioł I, Kotlęga D, et al. The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review. Int J Mol Sci. 2021;22(21):11644.
21. Yuui K, Kudo R, Kasuda S. Arterial thromboxane A2-induced transient contraction after IL-1β exposure. Eur J Inflamm. 2022;20.
22. Dorris SL, Peebles RS. PGI2 as a Regulator of Inflammatory Diseases. Mediators Inflamm. 2012;2012:1–9.
23. Sugimoto Y, Narumiya S. Prostaglandin E Receptors. Journal of Biological Chemistry. 2007;282(16):11613–11617.
24. Yang C-M, Yang C-C, Hsiao L-D, et al. Upregulation of COX-2 and PGE2 Induced by TNF-α Mediated Through TNFR1/MitoROS/PKCα/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts. J Inflamm Res. 2021;Volume 14:2807–2824
25. Neuschäfer-Rube F, Schön T, Kahnt I, et al. LDL-Dependent Regulation of TNFα/PGE2 Induced COX-2/mPGES-1 Expression in Human Macrophage Cell Lines. Inflammation. 2023;46(3):893–911.
26. Ariasnegrete S, Keller K, Chadee K. Proinflammatory Cytokines Regulate Cyclooxygenase-2 mRNA Expression in Human Macrophages. Biochem Biophys Res Commun. 1995;208(2):582–589.
27. Chabane N, Zayed N, Martel-Pelletier J, et al. Interleukin-1-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in human OA chondrocytes is associated with histone H3K4 methylation. J Transl Med. 2010;8(S1):P59.
28. Liu W, Reinmuth N, Stoeltzing O, et al. Cyclooxygenase-2 Is Up-Regulated by Interleukin-1β in Human Colorectal Cancer Cells via Multiple Signaling Pathways1. Cancer Res. 2003;63(13):3632–3636.
29. Kirkby NS, Zaiss AK, Wright WR, et al. Differential COX-2 induction by viral and bacterial PAMPs: Consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies. Biochem Biophys Res Commun. 2013;438(2):249–256.
30. Nagano S. Molecular mechanisms of lipopolysaccharide-induced cyclooxygenase-2 expression in human neutrophils: involvement of the mitogen-activated protein kinase pathway and regulation by anti-inflammatory cytokines. Int Immunol. 2002;14(7):733–740.
31. Arfeen M, Dhaked DK, Mani V. Multipotent Effect of Clozapine on Lipopolysaccharide-Induced Acetylcholinesterase, Cyclooxygenase-2,5-Lipoxygenase, and Caspase-3: In Vivo and Molecular Modeling Studies. Molecules. 2025;30(2):266.
32. Muñoz M, Sánchez A, Pilar Martínez M, et al. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. Free Radic Biol Med. 2015;84:77–90.
33. Onodera Y, Teramura T, Takehara T, et al. Reactive oxygen species induce Cox‐2 expression via TAK1 activation in synovial fibroblast cells. FEBS Open Bio. 2015;5(1):492–501.
34. Kiritoshi S, Nishikawa T, Sonoda K, et al. Reactive Oxygen Species from Mitochondria Induce Cyclooxygenase-2 Gene Expression in Human Mesangial Cells. Diabetes. 2003;52(10):2570–2577.
35. Kage K, Fujita N, Oh-hara T, et al. Basic Fibroblast Growth Factor Induces Cyclooxygenase-2 Expression in Endothelial Cells Derived from Bone. Biochem Biophys Res Commun. 1999;254(1):259–263.
36. Tessner TG, Muhale F, Schloemann S, et al. Basic fibroblast growth factor upregulates cyclooxygenase-2 in I407 cells through p38 MAP kinase. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2003;284(2):G269–G279.
37. Tamura M, Sebastian S, Gurates B, et al. Vascular Endothelial Growth Factor Up-Regulates Cyclooxygenase-2 Expression in Human Endothelial Cells. J Clin Endocrinol Metab. 2002;87(7):3504–3507.
38. Saha D, Datta PK, Sheng H, et al. Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells. Neoplasia. 1999;1(6):508–517.
39. Yang Y, Geng Y, Cheng X, et al. Cyclooxygenase 2 contributes to the hypoxia induced aggravation of the neuroinflammation response stimulated by lipopolysaccharide in microglia. Exp Ther Med. 2023;25(3):123.
40. Heikal L, Ferns G. Hypoxia, Angiogenesis and Atherogenesis. In: Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy InTech; 2017.
41. Zhang Y, Daaka Y. PGE2 promotes angiogenesis through EP4 and PKA Cγ pathway. Blood. 2011;118(19):5355–5364.
42. Hosono K, Isonaka R, Kawakami T, et al. Signaling of Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice. PLoS One 2016;11(10):e0162532.
43. Blitek A, Szymanska M, Morawska-Pucinska E, et al. Prostacyclin receptor (PTGIR) in the porcine endometrium: Regulation of expression and role in luminal epithelial and stromal cells. Theriogenology. 2015;84(6):969–982.
44. Szymanska M, Blitek A. Diverse effects of prostacyclin on angiogenesis-related processes in the porcine endometrium. Sci Rep. 2023;13(1):14133.
45. Ho AT V., Palla AR, Blake MR, et al. Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences. 2017;114(26):6675–6684.
46. Wang YX, Palla AR, Ho ATV, et al. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Cell Stem Cell. 2025;32(7):1154-1169.e9.
47. Correia MR, Han SW, Escalante T, et al. The role of the cyclooxygenase-2 pathway in tissue ischemia and revascularization following skeletal muscle injury induced by bothropic snake venom. Microvasc Res. 2025;157:104760.
48. Li J, Chen H, Xiong Q, et al. Celecoxib disrupts temporal coordination of TGF-β/α-SMA signaling in skeletal muscle repair: a time-dependent study of fibrosis and inflammation. Eur J Med Res. 2025;30(1):703.
49. Kim H-B, Kim M, Park Y-S, et al. Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice. Gastroenterology. 2017;152(3):616–630.
50. Huang M, Wang L, Chen J, et al. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1α is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. Int J Oncol. 2016;48(5):2144–2154.
51. Hashemi Goradel N, Najafi M, Salehi E, et al. Cyclooxygenase‐2 in cancer: A review. J Cell Physiol. 2019;234(5):5683–5699.
52. Huang H, Chen S, Cheng H, et al. The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model. J Nanobiotechnology. 2022;20(1):95.
53. Hugo HJ, Saunders C, Ramsay RG, et al. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis. J Mammary Gland Biol Neoplasia. 2015;20(3–4):109–119.
54. Yao C, Narumiya S. Prostaglandin‐cytokine crosstalk in chronic inflammation. Br J Pharmacol. 2019;176(3):337–354.
55. Chun K-S, Kim E-H, Kim D-H, et al. Targeting cyclooxygenase-2 for chemoprevention of inflammation-associated intestinal carcinogenesis: An update. Biochem Pharmacol. 2024;228:116259.
56. Tang Q, Chen L-L, Wei F, et al. Effect of 15-Deoxy-[INCREMENT]12,14-prostaglandin J2 Nanocapsules on Inflammation and Bone Regeneration in a Rat Bone Defect Model. Chin Med J. 2017;130(3):347–356.
