The need for discovering and assessing ACE2 Activators as Potential Targets for Treating Fibrosis: A Review of literature | ||||
| ARCADEs of MEDICINE | ||||
| Articles in Press, Accepted Manuscript, Available Online from 07 July 2025 | ||||
| Document Type: Review Articles | ||||
| DOI: 10.21608/arcmed.2025.381506.1122 | ||||
 View on SCiNiTO | ||||
| Authors | ||||
Ahmad Galal   1; Wagida Anwar2; Ebtehal El-Demerdash1; Rana Abdelnaby3
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| 1Department of Biomedical Research, Armed Forces College of Medicine, Cairo, Egypt | ||||
| 2Department of Biomedical Research, AFCM, Cairo, Egypt | ||||
| 3Department of pharmaceutical chemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt | ||||
| Abstract | ||||
| Background: Fibrosis is a pathological consequence of chronic organ injury characterized by excessive extracellular matrix deposition leading to tissue scarring and organ dysfunction. Angiotensin-converting enzyme 2 (ACE2) is a counter-regulatory component of the renin–angiotensin system that degrades angiotensin II to angiotensin-(1–7), shifting signaling towards anti-fibrotic pathways. Loss of ACE2 activity exacerbates fibrosis in multiple organs, whereas augmenting ACE2 activity can mitigate fibrogenesis. Main body: Recent research has focused on discovering ACE2 activators as a novel anti-fibrotic strategy. Structure-based drug design and high-throughput screening have identified several small-molecule ACE2 activators (e.g., xanthenone XNT and diminazene aceturate [DIZE]) and natural product-derived compounds (e.g., bile acid derivatives and phytochemicals) that enhance ACE2 activity. Preclinical studies in cardiac, renal, pulmonary, and hepatic fibrosis models demonstrate that ACE2 activation increases angiotensin-(1–7) signaling, reduces angiotensin II levels, and attenuates fibrotic remodeling and inflammation in vivo. ACE2 activators broadly fall into synthetic allosteric molecules, repurposed drugs, and indirect up-regulators of ACE2 expression. These agents have shown improved cardiac function and reduced collagen deposition in heart failure models, nephroprotection in chronic kidney injury, protection against bleomycin-induced lung fibrosis, and decreased liver fibrosis in cholestatic injury models. ACE2 activation appears well-tolerated in animals, though specificity and optimal delivery remain challenges. Conclusion: Targeting ACE2 with activators represents a promising therapeutic avenue to counter fibrosis by restoring the balance of profibrotic and antifibrotic RAS signaling. Ongoing advancements in ACE2 activator design and testing support their potential to become innovative treatments for fibrotic diseases, pending further preclinical validation and clinical trials. | ||||
| Keywords | ||||
| ACE2 activator; fibrosis; antifibrotic therapy; renin–angiotensin system; allosteric activation | ||||
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