Al-Kadi A, Anter A, Rofaeil RR, Sayed-Ahmed MM, Ahmed ASF. Klotho: A multifaceted protector in sepsis-induced organ damage and a potential therapeutic target. World J Crit Care Med 2025; 14(3): 103458 [DOI: 10.5492/wjccm.v14.i3.103458]
Corresponding Author of This Article
Al-Shaimaa F Ahmed, PhD, Associate Professor, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Cairo-Aswan Agriculture Road, Minia 61511, Egypt. shaimaa.faissal@minia.edu.eg
Research Domain of This Article
Pharmacology & Pharmacy
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Crit Care Med. Sep 9, 2025; 14(3): 103458 Published online Sep 9, 2025. doi: 10.5492/wjccm.v14.i3.103458
Klotho: A multifaceted protector in sepsis-induced organ damage and a potential therapeutic target
Alaa Al-Kadi, Aliaa Anter, Remon R Rofaeil, Mohamed M Sayed-Ahmed, Al-Shaimaa F Ahmed
Alaa Al-Kadi, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Deraya University, Minia 61511, Egypt
Aliaa Anter, Al-Shaimaa F Ahmed, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt
Remon R Rofaeil, Department of Medical Pharmacology, Faculty of Medicine, Minia University, Minia 61511, Egypt
Remon R Rofaeil, Department of Pharmacology and Toxicology, Deraya University, Minia 61511, Egypt
Mohamed M Sayed-Ahmed, Pharmacology and Experimental Oncology Unit, National Cancer Institute, Cairo University, Cairo 11435, Egypt
Author contributions: Al-Kadi A was responsible for design of the experiment, execution of experiments, sample collection, data handling, and manuscript writing; Al-Kadi A, Anter A, Rofaeil RR, Sayed-Ahmed MM, Ahmed ASF were responsible for design of the experiment, supervision, and manuscript revision; all authors have contributed to and approved the final manuscript.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Al-Shaimaa F Ahmed, PhD, Associate Professor, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Cairo-Aswan Agriculture Road, Minia 61511, Egypt. shaimaa.faissal@minia.edu.eg
Received: November 20, 2024 Revised: March 4, 2025 Accepted: March 11, 2025 Published online: September 9, 2025 Processing time: 241 Days and 1 Hours
Abstract
Sepsis is a life-threatening organ dysfunction associated with a robust systemic inflammatory and immune response to infection. Its pathological consequences lead to multiple organ deficits. Klotho was initially introduced as an antiaging molecule. Its deficiency significantly reduces lifespan, and its overexpression protects against organ injury. It reduces oxidative stress and apoptosis and has anti-inflammatory and antifibrotic properties. In this review, we discuss the underlying mechanisms of sepsis-related klotho down-regulation and the protective role of klotho in sepsis. In developing sepsis-induced multiple organ damage, klotho can modulate multiple downstream signals including nuclear factor-kappa β, mitogen activated protein kinase, and apoptosis. Multiple studies show klotho's protective effects in sepsis through activation of nuclear factor erythroid-related factor 2, Forkhead transcription factor O, and restoration of internal antioxidant activity. The proposed protective action of klotho is a promising therapeutic strategy for managing sepsis and ameliorating its related organ damage.
Core Tip: Klotho, originally identified as an anti-aging protein, plays a critical role in mitigating sepsis-induced organ dysfunction by reducing oxidative stress, inflammation, and apoptosis. This review highlights klotho's potential as a therapeutic target, exploring its ability to modulate key signaling pathways like nuclear factor-kappa β, mitogen activated protein kinase, and nuclear factor erythroid-related factor 2. Reduced klotho levels correlate with increased severity of sepsis, while its supplementation shows promise in improving survival rates and alleviating organ damage. Understanding the mechanisms of klotho's cytoprotective effects may pave the way for novel treatments in managing sepsis-related organ failure.
