Anti-oxidative stress treatment and current clinical trials.

With great interest, we read a recently published review paper authored by Li et al [ 1 ], discussing the progress of using herbal extracts from traditional Chinese medicine as a therapeutic method to treat liver fibrosis via inhibiting oxidative stress. We agree with the authors that oxidative stress is a critical factor that can be targeted in the treatment of liver fibrosis. Oxidative stress is caused by an imbalance between the production and accumulation of reactive oxygen species (ROS) and the biological system to detoxify ROS products[ 2 ]. The accumulation of ROS can cause cell damage through the destruction of proteins and lipids, genetic modification, and disturbance of cellular signaling[ 2 , 3 ]. Therefore, oxidative stress has been recognized as a crucial factor involved in the underlying mechanisms of disease development and progression[ 4 ]. In fact, oxidative stress has gained more and more attraction recently due to its important roles in many diseases, such as heart disease[ 5 ], cancer[ 6 ], hypertension[ 7 ], cardiovascular diseases[ 8 ], aging[ 9 ], neurodegenerative disease[ 10 , 11 ], Alzheimer's disease[ 12 ], Parkinson’s disease[ 13 ], and metabolic disorders. Moreover, oxidative stress also plays a pivotal role in organ transplantation[ 14 ] and infectious diseases[ 15 ]. Therefore, anti-oxidative stress as a therapeutic strategy has gained more attention for disease treatment. Accumulating studies are performed to decipher the mechanism of oxidative stress in disease. Oxidative stress inducers include endogenous sources and exposomes[ 16 ]. Endogenous sources can induce the endoplasmic reticulum stress that may be caused by misfolded proteins, resulting in elevated levels of ROS[ 17 ]. The exposomes include but are not limited to toxins, irradiation exposure, air pollution, smoking, nutrients, chemicals, and infection[ 18 ]. Upon exposure to oxidant sources, the cellular nucleus undergoes several biological processes (Figure 1 ), such as stress adaption via the forkhead box signaling pathway[ 19 ], inflammatory responses through the nuclear factor (NF)-κB and inhibitor of NF-κB kinase signaling pathway[ 20 , 21 ], hypoxic responses controlled by hypoxia-inducible facto-prolyl hydroxylase domain proteins[ 22 ], DNA repair or apoptosis process through the p53 signaling pathway[ 23 ], and antioxidant responses through the Kelch-like ECH-associated protein 1 (KEAP1)-transcription factor NF-E2 p45-related factor 2 (NRF2) (KEAP1-NRF2) signaling pathway[ 24 ]. The mitochondrion serves as an important organelle to generate ATP as an energy source, and ROS is also produced in this process. The accumulated excessive levels of ROS can result in oxidative stress[ 25 ]. Thus, the imbalance of the production of excessive oxidants and antioxidant processes leads to disease development and progression. Diagram illustrating reactive oxygen species including inducers, mechanisms, related diseases, and clinical trial treatments. Inducers include endogenous and exposomes. The mechanism includes the cell nucleus response to exposure to reactive oxygen species (ROS) and the mitochondrial ROS response. The imbalance between the accumulation of ROS and their clearance by the biological system results in ROS-related diseases such as heart disease, cancer, hypertension, cardiovascular diseases, Alzheimer’s disease, aging, neurodegenerative disease Parkinson’s disease, and metabolic disorder. Current clinical trials mainly focus on the drug and dietary invention. ER stress: Endoplasmic reticulum stress; ROS: Reactive oxygen species; IKK-NF-κB: IκB kinase-nuclear factor-κB; HIF-PDHs: Hypoxia-inducible factor-prolyl hydroxylase domain proteins; p53: Tumor protein p53 or transformation-related protein 53; KEAP1-NRF2: Kelch-like ECH-associated protein 1-nuclear factor E2-related factor 2. All cartoons in this figure were prepared using Biorender ( https://biorender.com , accessed on 7 January 2024). Inspired by this published review article, here, we give a further discussion on the current clinical trials that are related to anti-oxidative stress in different diseases using various intervention methods. Currently, two major categories including dietary supplement and drug treatment are used in clinical trials and summarized in this letter (Table 1 ). The most tested drug in these clinical trials is N-acetylcysteine with application in different diseases, such as cancer (melanoma and leukemia), pulmonary disease, renal disease, liver diseases such as non-alcoholic fatty liver disease, infectious diseases including severe acute respiratory syndrome coronavirus and human immunodeficiency virus infections, obesity, Parkinson's disease, and depressive disorders. The drug melatonin has also been used in many diseases, such as necrotizing enterocolitis, multiple sclerosis, and septic shock. Curcumin is a dietary supplement, which has been tested for renal transplantation disorder, coronary artery disease, metabolic syndrome, kidney disease, and others (Table 1 ). The data were collected from the website https://clinicaltrials.gov (accessed on October 28, 2023) using the keywords anti-oxidative stress, disease, and treatments such as drugs and nutrients, including ongoing and completed clinical trials. Clinical trials on anti-oxidative stress-related treatment NAFLD: Non-alcoholic fatty liver disease; NA: Not applicable. In summary, oxidative stress is involved in many diseases and functions as a promising target in disease treatment and therapeutic drug screening. More potent antioxidants are expected to be explored to improve treatment outcomes. Meanwhile, the synergistic application of anti-oxidative drugs is an option to improve the therapeutic efficacy of other drugs.