Mitochondria-targeted natural products with potential for the treatment of mitochondria-related diseases

Abstract

Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.

Keywords

Mitochondrial dynamics / Natural products / Mitochondrial quality control / Oxidative phosphorylation / Apoptosis / Bioavailability

Funding

This work was supported by the Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (No. JYB2025XDXM609) and CAMS Innovation Fund for Medical Sciences (Nos. 2023-I2M-2-006, 2022-I2M-2-002, and 2021-I2M-1-028).

Declaration of Interest statement

The authors declare no competing financial interest.

Supporting information

Supporting information for this work can be obtained by contacting the corresponding authors via E-mail.

References

[1] Jahn H, Bartoš L, Dearden GI, et al. Phospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase. Nat Commun. 2023; 14(1):8115. https://doi.org/10.1038/s41467-023-43570-.

[2] Xian H, Liou YC. Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy. Cell Death Differ. 2021; 28(3):827-842. https://doi.org/10.1038/s41418-020-00657-.

[3] Chang X, Li YK, Cai C, et al. Mitochondrial quality control mechanisms as molecular targets in diabetic heart. Metabolism. 2022; 137:155313. https://doi.org/10.1016/j.metabol.2022.155313.

[4] Rizzuto R, De Stefani D, Raffaello A, et al. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012; 13(9):566-578. https://doi.org/10.1038/nrm3412.

[5] Bernardi P, Gerle C, Halestrap AP, et al. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions. Cell Death Differ. 2023; 30(8):1869-1885. https://doi.org/10.1038/s41418-023-01187-0.

[6] Kalkavan H, Green DR. MOMP, cell suicide as a BCL-2 family business. Cell Death Differ. 2018; 25(1):46-55. https://doi.org/10.1038/cdd.2017.179.

[7] Chen W, Zhao HK, Li YS. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023; 8(1):333. https://doi.org/10.1038/s41392-023-01547-9.

[8] Popov LD.Mitochondrial biogenesis: An update. J Cell Mol Med. 2020; 24(9):4892-4899. https://doi.org/10.1111/jcmm.15194.

[9] Iwabu M, Yamauchi T, Okada-Iwabu M, et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca²⁺ and AMPK/SIRT1. Nature. 2010; 464(7293):1313-1319. https://doi.org/10.1038/nature08991.

[10] Xu RJ, Hu Q, Ma Q, et al. The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway. Cell Death Dis. 2014; 5(8):e1373. https://doi.org/10.1038/cddis.2014.328.

[11] Wang L, Yang MM, Jin HH. PI3K/AKT phosphorylation activates ERRα by upregulating PGC-1α and PGC-1β in gallbladder cancer. Mol Med Rep. 2021; 24(2):613. https://doi.org/10.3892/mmr.2021.12252.

[12] Falkenberg M, Larsson NG, Gustafsson CM. Replication and transcription of human mitochondrial DNA. Annu Rev Biochem. 2024; 93(1):47-77. https://doi.org/10.1146/annurev-biochem-052621-092014.

[13] Wanrooij S, Luoma P, van Goethem G, et al. Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res. 2004; 32(10):3053-3064. https://doi.org/10.1093/nar/gkh634.

[14] Wong LJ, Naviaux RK, Brunetti-Pierri N, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008; 29(9):E150-E172. https://doi.org/10.1002/humu.20824.

[15] Wang J, El-Hattab AW, Wong LJC.TK2-related mitochondrial DNA aaintenance defect, myopathic form. In: Adam MP, Bick S, Mirzaa GM, et al. eds. GeneReviews^®. Seattle (WA): University of Washington, Seattle; December 6, 2012. https://www.ncbi.nlm.nih.gov/books/NBK114628/

[16] El-Hattab AW, Scaglia F. Deoxyguanosine kinase deficiency. In: Adam MP, Bick S, Mirzaa GM, et al. eds. GeneReviews^®. Seattle (WA): University of Washington, Seattle; June 18, 2009. https://www.ncbi.nlm.nih.gov/books/NBK7040/

[17] Greenberg-Kushnir N, Grossmann LD, Barg AA, et al. Long-term hematopoietic dysfunction in patients with large-scale mitochondrial DNA deletion syndromes. Pediatr Blood Cancer. 2025; 72(1):e31383. https://doi.org/10.1002/pbc.31383.

[18] Ripolone M, Ronchi D, Violano R, et al. Impaired muscle mitochondrial biogenesis and myogenesis in spinal muscular atrophy. JAMA Neurol. 2015; 72(6):666-675. https://doi.org/10.1001/jamaneurol.2015.0178.

[19] Affourtit C, Carré JE.Mitochondrial involvement in sarcopenia. Acta Physiol (Oxf). 2024; 240(3):e14107. https://doi.org/10.1111/apha.14107.

[20] Carelli V, La Morgia C, Sadun AA. Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options. Curr Opin Neurol. 2013; 26(1):52-58. https://doi.org/10.1097/WCO.0b013e32835c5f0b.

[21] Brown DA, Perry JB, Allen ME, et al. Expert consensus document: mitochondrial function as a therapeutic target in heart failure. Nat Rev Cardiol. 2017; 14(4):238-250. https://doi.org/10.1038/nrcardio.2016.203.

[22] Oka SI, Sabry AD, Cawley KM, et al. Multiple levels of PGC-1α dysregulation in heart failure. Front Cardiovasc Med. 2020; 7:2. https://doi.org/10.3389/fcvm.2020.00002.

[23] Khan MP, Singh AK, Joharapurkar AA, et al. Pathophysiological mechanism of bone loss in T2DM involves inverse regulation of osteoblast function by PGC-1α and skeletal muscle atrogenes: AdipoR1 as a potential target for reversing diabetes-induced osteopenia. Diabetes. 2015; 64(7):2609-2623. https://doi.org/10.2337/db14-1611.

[24] Palikaras K, Lionaki E, Tavernarakis N. Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ. 2015; 22(9):1399-1401. https://doi.org/10.1038/cdd.2015.86.

[25] Yang M, Wei X, Yi X, et al. Mitophagy-related regulated cell death: molecular mechanisms and disease implications. Cell Death Dis. 2024; 15(7):505. https://doi.org/10.1038/s41419-024-06804-5.

[26] Lazarou M, Jin SM, Kane LA, et al. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev Cell. 2012; 22(2):320-333. https://doi.org/10.1016/j.devcel.2011.12.014.

[27] Lazarou M, Sliter DA, Kane LA, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015; 524(7565):309-314. https://doi.org/10.1038/nature14893.

[28] Elcocks H, Brazel AJ, McCarron KR, et al. FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. EMBO J. 2023; 42(13):e112799. https://doi.org/10.15252/embj.2022112799.

[29] Jin QH, Li RB, Hu N, et al. DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol. 2018; 14:576-587. https://doi.org/10.1016/j.redox.2017.11.004.

[30] Shi DD, Guo XC, Ning ZQ, et al. Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer’s disease. Front Aging Neurosci. 2025; 17:1544241. https://doi.org/10.3389/fnagi.2025.1544241.

[31] Chen G, Han Z, Feng D, et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell. 2014; 54(3):362-377. https://doi.org/10.1016/j.molcel.2014.02.034.

[32] Wang JY, Zhuang HW, Jia LQ, et al. Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy. Int J Biol Sci. 2024; 20(11):4458-4475. https://doi.org/10.7150/ijbs.95853.

[33] Yan CJ, Gong LL, Chen L, et al. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy. 2020; 16(3):419-434. https://doi.org/10.1080/15548627.2019.1628520.

[34] Wang JY, Zhuang HW, Li C, et al. Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance. J Nanobiotechnology. 2025; 23(1):383. https://doi.org/10.1186/s12951-025-03420-.

[35] Barazzuol L, Giamogante F, Brini M, et al. PINK1/Parkin mediated mitophagy, Ca²⁺ signalling, and ER-mitochondria contacts in Parkinson’s disease. Int J Mol Sci. 2020; 21(5):1772. https://doi.org/10.3390/ijms21051772.

[36] Faruk MO, Ichimura Y, Kageyama S, et al. Phase-separated protein droplets of amyotrophic lateral sclerosis-associated p62/SQSTM1 mutants show reduced inner fluidity. J Biol Chem. 2021; 297(6):101405. https://doi.org/10.1016/j.jbc.2021.101405.

[37] Wen D, Li QS, Li YY, et al. OPTN deficiency through CRISPR/Cas9 downregulates autophagy and mitophagy in a SOD1-G93A-expressing transgenic cell line. IBRO Neurosci Rep. 2025; 19:307-316. https://doi.org/10.1016/j.ibneur.2025.07.011.

[38] Xia J, Jin J, Dai S, et al. Mitophagy: a key regulator of radiotherapy resistance in the tumor immune microenvironment. Mol Aspects Med. 2025; 105:101385. https://doi.org/10.1016/j.mam.2025.101385.

[39] Zhou XG, Wang J, Yu L, et al. Mitophagy and cGAS-STING crosstalk in neuroinflammation. Acta Pharm Sin B. 2024; 14(8):3327-3361. https://doi.org/10.1016/j.apsb.2024.05.012.

[40] Lee H, Smith SB, Yoon Y. The short variant of the mitochondrial dynamin OPA 1 maintains mitochondrial energetics and cristae structure. J Biol Chem. 2017; 292(17):7115-7130. https://doi.org/10.1074/jbc.M116.762567.

[41] Escobar-Henriques M, Joaquim M. Mitofusins: disease gatekeepers and hubs in mitochondrial quality control by E3 ligases. Front Physiol. 2019; 10:517. https://doi.org/10.3389/fphys.2019.00517.

[42] Wang Y, Serricchio M, Jauregui M, et al. Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy. 2015; 11(4):595-606. https://doi.org/10.1080/15548627.2015.1034408.

[43] Rainbolt TK, Lebeau J, Puchades C, et al. Reciprocal degradation of YME1L and OMA1 adapts mitochondrial proteolytic activity during stress. Cell Rep. 2016; 14(9):2041-2049. https://doi.org/10.1016/j.celrep.2016.02.011.

[44] Frank S. Dysregulation of mitochondrial fusion and fission: an emerging concept in neurodegeneration. Acta Neuropathol. 2006; 111(2):93-100. https://doi.org/10.1007/s00401-005-0002-3.

[45] Burtscher M, Burtscher J. MFN2: Shaping mitochondria and cardiac adaptations to hypoxia. Acta Physiol (Oxf). 2023; 239(2):e14026. https://doi.org/10.1111/apha.14026.

[46] Kleele T, Rey T, Winter J, et al. Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature. 2021; 593(7859):435-439. https://doi.org/10.1038/s41586-021-03510-6.

[47] Simula L, Corrado M, Accordi B, et al. JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction. Cell Death Differ. 2020; 27(10):2749-2767. https://doi.org/10.1038/s41418-020-0540-1.

[48] Xu HX, Wang X, Yu WJ, et al. Syntaxin 17 protects against heart failure through recruitment of CDK 1 to promote DRP1-dependent mitophagy. JACC Basic Transl Sci. 2023; 8(9):1215-1239. https://doi.org/10.1016/j.jacbts.2023.04.006.

[49] Cha Y, Kim T, Jeon J, et al.SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell Rep. 2021; 37(13):110155. https://doi.org/10.1016/j.celrep.2021.110155.

[50] Zhang JD, Feng JC, Ma D, et al. Neuroprotective mitochondrial remodeling by AKAP121/PKA protects HT22 cell from glutamate-induced oxidative stress. Mol Neurobiol. 2019; 56(8):5586-5607. https://doi.org/10.1007/s12035-018-1464-3.

[51] Hanada Y, Maeda R, Ishihara T, et al. Alternative splicing of Mff regulates AMPK-mediated phosphorylation, mitochondrial fission and antiviral response. Pharmacol Res. 2024; 209:107414. https://doi.org/10.1016/j.phrs.2024.107414.

[52] Berti B, Verrigni D, Nasca A, et al. De Novo DNM1L mutation in a patient with encephalopathy, cardiomyopathy and fatal non-epileptic paroxysmal refractory vomiting. Int J Mol Sci. 2024; 25(14):7782. https://doi.org/10.3390/ijms25147782.

[53] Koch J, Feichtinger RG, Freisinger P, et al. Disturbed mitochondrial and peroxisomal dynamics due to loss of MFF causes Leigh-like encephalopathy, optic atrophy and peripheral neuropathy. J Med Genet. 2016; 53(4):270-278. https://doi.org/10.1136/jmedgenet-2015-103500.

[54] Zhao RZ, Jiang S, Zhang L, et al.Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med. 2019; 44(1):3-15. https://doi.org/10.3892/ijmm.2019.4188.

[55] Zhang YK, Fan YC, Hu HL, et al. ZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury. Nat Commun. 2023; 14(1):7527. https://doi.org/10.1038/s41467-023-43439-0.

[56] Venit T, Sapkota O, Abdrabou WS, et al. Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice. Nat Commun. 2023; 14(1):6328. https://doi.org/10.1038/s41467-023-42093-.

[57] Allen AR, Jones A', LoBianco FV, et al. Effect of Sirt3 on hippocampal MnSOD activity, mitochondrial function, physiology, and cognition in an aged murine model. Behav Brain Res. 2023; 444:114335. https://doi.org/10.1016/j.bbr.2023.114335.

[58] Signorile A, Pacelli C, Palese LL, et al. cAMP/PKA signaling modulates mitochondrial supercomplex organization. Int J Mol Sci. 2022; 23(17):9655. https://doi.org/10.3390/ijms23179655

[59] Schubert Baldo M, Vilarinho L. Molecular basis of Leigh syndrome: a current look. Orphanet J Rare Dis. 2020; 15(1):31. https://doi.org/10.1186/s13023-020-1297-9.

[60] James AM, Wei YH, Pang CY, et al. Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations. Biochem J. 1996; 318(Pt 2):401-407. https://doi.org/10.1042/bj3180401

[61] Brischigliaro M, Frigo E, Corrà S, et al. Modelling of BCS1L-related human mitochondrial disease in Drosophila melanogaster. J Mol Med (Berl). 2021; 99(10):1471-1485. https://doi.org/10.1007/s00109-021-02110-1.

[62] van der Westhuizen FH, Smet J, Levanets O, et al. Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia. J Inherit Metab Dis. 2010;33Suppl 3:S55-S62. https://doi.org/10.1007/s10545-009-9020-y

[63] Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov. 2004; 3(3):205-214. https://doi.org/10.1038/nrd1330.244.

[64] D'Oria R, Schipani R, Leonardini A, et al. The role of oxidative stress in cardiac disease: from physiological response to injury factor. Oxid Med Cell Longev. 2020; 2020:5732956. https://doi.org/10.1155/2020/5732956.

[65] Sharma R, Reinstadler B, Engelstad K, et al. Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity. J Clin Invest. 2021; 131(2):e136055. https://doi.org/10.1172/JCI136055.

[66] Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020; 21(2):85-100. https://doi.org/10.1038/s41580-019-0173-8.

[67] Ermak G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002; 38(10):713-721. https://doi.org/10.1016/s0161-5890(01)00108-.

[68] Kroemer G, Martin SJ. Caspase-independent cell death. Nat Med. 2005; 11(7):725-730. https://doi.org/10.1038/nm1263.

[69] Mandic A, Viktorsson K, Strandberg L, et al. Calpain-mediated Bid cleavage and calpain-independent Bak modulation: two separate pathways in cisplatin-induced apoptosis. Mol Cell Biol. 2002; 22(9):3003-3013. https://doi.org/10.1128/MCB.22.9.3003-3013.2002.

[70] Wang HG, Pathan N, Ethell IM, et al. Ca²⁺-induced apoptosis through calcineurin dephosphorylation of BAD. Science. 1999; 284(5412):339-343. https://doi.org/10.1126/science.284.5412.339.

[71] Yang K, Zhang P, Li JX, et al. Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury. J Pharm Anal. 2024; 14(11):101034. https://doi.org/10.1016/j.jpha.2024.101034.

[72] Pu XY, Wu QM, Yan ZQ, et al. Tanshinone IIA modulates Sirt5 and Metll3 interaction to govern mitochondria-endoplasmic reticulum unfolded protein response in coronary microvascular injury. Phytomedicine. 2025; 145:156982. https://doi.org/10.1016/j.phymed.2025.156982.

[73] Chang X, Zhou SY, Huang Y, et al. Zishen Huoxue decoction (ZSHX) alleviates ischemic myocardial injury (MI) via Sirt5-β-tubulin mediated synergistic mechanism of "mitophagy-unfolded protein response" and mitophagy. Chin J Nat Med. 2025; 23(3):311-321. https://doi.org/10.1016/S1875-5364(25)60838-.

[74] Shen Y, Gao X, Xiang Y, et al. Exploiting mitochondria by triggering a faulty unfolded protein response leads to effective cardioprotection. Int J Med Sci. 2025; 22(1):188-196. https://doi.org/10.7150/ijms.100523.

[75] Logan CV, Szabadkai G, Sharpe JA, et al. Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet. 2014; 46(2):188-193. https://doi.org/10.1038/ng.2851.

[76] Boyman L, Karbowski M, Lederer WJ. Regulation of mitochondrial ATP production: Ca²⁺ signaling and quality control. Trends Mol Med. 2020; 26(1):21-39. https://doi.org/10.1016/j.molmed.2019.10.007.

[77] Vallese F, Barazzuol L, Maso L, et al. ER-mitochondria calcium transfer, organelle contacts and neurodegenerative diseases. Adv Exp Med Biol. 2020; 1131:719-746. https://doi.org/10.1007/978-3-030-12457-1_29.

[78] Pang BX, Dong GT, Pang TL, et al. Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction. Angiogenesis. 2024; 27(4):623-639. https://doi.org/10.1007/s10456-024-09938-4.

[79] Pang BX, Dong GT, Pang TL, et al. Advances in pathogenesis and treatment of vascular endothelial injury-related diseases mediated by mitochondrial abnormality. Front Pharmacol. 2024; 15:1422686. https://doi.org/10.3389/fphar.2024.1422686.

[80] Chang X, Zhang Q, Pu XY, et al. The effect of unhealthy lifestyle on the pathogenesis of sick sinus syndrome: a life-guiding review. Medicine (Baltimore). 2024; 103(43):e39996. https://doi.org/10.1097/MD.0000000000039996.

[81] Jin JY, Wei XX, Zhi XL, et al. Drp1-dependent mitochondrial fission in cardiovascular disease. Acta Pharmacol Sin. 2021; 42(5):655-664. https://doi.org/10.1038/s41401-020-00518-.

[82] Bagur R, Tanguy S, Foriel S, et al. The impact of cardiac ischemia/reperfusion on the mitochondria-cytoskeleton interactions. Biochim Biophys Acta. 2016; 1862(6):1159-1171. https://doi.org/10.1016/j.bbadis.2016.03.009.

[83] Wu QM, Wang YL, Liu JF, et al. Microtubules and cardiovascular diseases: insights into pathology and therapeutic strategies. Int J Biochem Cell Biol. 2024; 175:106650. https://doi.org/10.1016/j.biocel.2024.106650.

[84] Li Y, Wei X, Liu SL, et al. Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3. Phytother Res. 2021; 35(8):4579-4591. https://doi.org/10.1002/ptr.7175.

[85] Xue HY, Li PP, Luo YS, et al. Salidroside stimulates the Sirt1/PGC-1α axis and ameliorates diabetic nephropathy in mice. Phytomedicine. 2019; 54:240-247. https://doi.org/10.1016/j.phymed.2018.10.031.

[86] Mao GX, Xu XG, Wang SY, et al. Salidroside delays cellular senescence by stimulating mitochondrial biogenesis partly through a miR-22/SIRT-1 pathway. Oxid Med Cell Longev. 2019; 2019:5276096. https://doi.org/10.1155/2019/5276096.

[87] Chang WG, Zhang M, Li J, et al. Berberine improves insulin resistance in cardiomyocytes via activation of 5'-adenosine monophosphate-activated protein kinase. Metabolism. 2013; 62(8):1159-1167. https://doi.org/10.1016/j.metabol.2013.02.007.

[88] Liu CS, Zheng YR, Zhang YF, et al. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia. 2016; 109:274-282. https://doi.org/10.1016/j.fitote.2016.02.001.

[89] Chen J, Wong HS, Leong PK, et al. Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: a possible mechanism underlying its beneficial effect on exercise endurance. Food Funct. 2017; 8(7):2425-2436. https://doi.org/10.1039/c7fo00127.

[90] Clinicaltrials. gov. Study Testing Benefits of Ursolic Acid (UA) as a Countermeasure To Myopenia and Insulin Resistance in Chronic Spinal Cord Injury (SCI). Accessed 22 September 2025. https://www.clinicaltrials.gov/study/NCT05776862.

[91] Niu WJ, Wang HB, Wang B, et al. Resveratrol improves muscle regeneration in obese mice through enhancing mitochondrial biogenesis. J Nutr Biochem. 2021; 98:108804. https://doi.org/10.1016/j.jnutbio.2021.108804.

[92] Wang P, Sang SM. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors. 2018; 44(1):16-25. https://doi.org/10.1002/biof.1410.

[93] Zhang JW, LvQ W, Liu XY, et al. Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator. Br J Pharmacol. 2024; 181(18):3346-3363. https://doi.org/10.1111/bph.16403.

[94] Jeong MH, Tran NK, Kwak TH, et al. β-Lapachone ameliorates lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. PLoS One. 2014; 9(3):e91039. https://doi.org/10.1371/journal.pone.0091039

[95] Nadal X, Del Río C, Casano S, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017; 174(23):4263-4276. https://doi.org/10.1111/bph.14019.

[96] Tham YY, Choo QC, Muhammad TST, et al. Lauric acid alleviates insulin resistance by improving mitochondrial biogenesis in THP-1 macrophages. Mol Biol Rep. 2020; 47(12):9595-9607. https://doi.org/10.1007/s11033-020-06019-9.

[97] Zhang WX, Wang Y, Chen L, et al. Dihydroartemisinin suppresses glioma growth by repressing ERRα-mediated mitochondrial biogenesis. Mol Cell Biochem. 2024; 479(10):2809-2825. https://doi.org/10.1007/s11010-023-04892-.

[98] Fan SQ, Yan XM, Hu XX, et al. Shikonin blocks CAF-induced TNBC metastasis by suppressing mitochondrial biogenesis through GSK-3β/NEDD4-1 mediated phosphorylation-dependent degradation of PGC-1α. J Exp Clin Cancer Res. 2024; 43(1):180. https://doi.org/10.1186/s13046-024-03101-.

[99] Wang CL, Zou Q, Pu YS, et al. Berberine rescues D-ribose-induced Alzheimer’s pathology via promoting mitophagy. Int J Mol Sci. 2023; 24(6):5896. https://doi.org/10.3390/ijms24065896.

[100] Wang L, Tang XQ, Shi Y, et al. Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy. Acta Pharmacol Sin. 2023; 44(2):332-344. https://doi.org/10.1038/s41401-022-00956-.

[101] Liu NY, Ding YQ, Zhou H, et al. Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome. Int J Med Sci. 2024; 21(3):547-561. https://doi.org/10.7150/ijms.90484.

[102] Wang JY, Pu XY, Zhuang HW, et al. Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy. J Adv Res. 2025; 75:561-580. https://doi.org/10.1016/j.jare.2024.10.030.

[103] Cui S, Chen TT, Wang MM, et al. Tanshinone I inhibits metastasis of cervical cancer cells by inducing BNIP3/NIX-mediated mitophagy and reprogramming mitochondrial metabolism. Phytomedicine. 2022; 98:153958. https://doi.org/10.1016/j.phymed.2022.153958.

[104] Ma ZC, Chen WJ, Liu YD, et al. Artesunate sensitizes human hepatocellular carcinoma to sorafenib via exacerbating AFAP1L2-SRC-FUNDC1 axis-dependent mitophagy. Autophagy. 2024; 20(3):541-556. https://doi.org/10.1080/15548627.2023.2261758.

[105] Chang X, Zhou H, Hu JL, et al. Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression. Int J Biol Sci. 2024; 20(14):5793-5811. https://doi.org/10.7150/ijbs.102424.

[106] Zheng DX, Chen LL, Li GP, et al. Fucoxanthin ameliorated myocardial fibrosis in STZ-induced diabetic rats and cell hypertrophy in HG-induced H9c2 cells by alleviating oxidative stress and restoring mitophagy. Food Funct. 2022; 13(18):9559-9575. https://doi.org/10.1039/d2fo01761.

[107] Clinicaltrials. gov. Effect of Fucoxanthin on the Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion. Accessed 22 September 2025. https://www.clinicaltrials.gov/study/NCT03613740.

[108] Li Y, Chen HX, Xie X, et al. PINK1-mediated mitophagy promotes oxidative phosphorylation and redox homeostasis to induce drug-tolerant persister cancer cells. Cancer Res. 2023; 83(3):398-413. https://doi.org/10.1158/0008-5472.CAN-22-2370.

[109] Huang YJ, Liang BX, Li ZM, et al. Polystyrene nanoplastic exposure induces excessive mitophagy by activating AMPK/ULK1 pathway in differentiated SH-SY5Y cells and dopaminergic neurons in vivo. Part Fibre Toxicol. 2023; 20(1):44. https://doi.org/10.1186/s12989-023-00556-4.

[110] Dera AA, Al Fayi M, Otifi H, et al. Thymoquinone (Tq) protects necroptosis induced by autophagy/mitophagy-dependent oxidative stress in human bronchial epithelial cells exposed to cigarette smoke extract (CSE). J Food Biochem. 2020; 44(9):e13366. https://doi.org/10.1111/jfbc.13366.

[111] Ouyang F, Li YL, Wang HM, et al. Aloe emodin alleviates radiation-induced heart disease via blocking P4HB lactylation and mitigating kynurenine metabolic disruption. Adv Sci (Weinh). 2024; 11(47):e2406026. https://doi.org/10.1002/advs.202406026.

[112] Fan YN, Chen ZW, Wang HX, et al. Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis. Bone Res. 2025; 13(1):18. https://doi.org/10.1038/s41413-024-00390-0.

[113] Zhou J, Li GB, Zheng Y, et al. A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission. Autophagy. 2015; 11(8):1259-1279. https://doi.org/10.1080/15548627.2015.1056970.

[114] Zhang CG, Wang RC, Liu ZY, et al. The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1’s association with the mitochondrial protein TOM20. J Biol Chem. 2019; 294(18):7472-7487. https://doi.org/10.1074/jbc.RA118.006506.

[115] Hu MJ, Luo Q, Alitongbieke G, et al. Celastrol-induced Nur 77 interaction with TRAF2 alleviates inflammation by promoting mitochondrial ubiquitination and autophagy. Mol Cell. 2017; 66(1):141-153.e6. https://doi.org/10.1016/j.molcel.2017.03.008.

[116] Shi Y, Fang Q, Hu Y, et al. Melatonin ameliorates post-stroke cognitive impairment in mice by inhibiting excessive mitophagy. Cells. 2024; 13(10):872. https://doi.org/10.3390/cells13100872.

[117] Lin XB, Fei MZ, Huang AX, et al. Breviscapine protects against pathological cardiac hypertrophy by targeting FOXO3a-mitofusin-1 mediated mitochondrial fusion. Free Radic Biol Med. 2024; 212:477-492. https://doi.org/10.1016/j.freeradbiomed.2024.01.007.

[118] Lin YZ, Lu ZY, Liang XH, et al. Effect of breviscapine against hepatic ischemia reperfusion injury. J Surg Res. 2016; 203(2):268-274. https://doi.org/10.1016/j.jss.2016.02.013.

[119] Wu L, Li Q, Liu SM, et al. Protective effect of hyperoside against renal ischemia-reperfusion injury via modulating mitochondrial fission, oxidative stress, and apoptosis. Free Radic Res. 2019; 53(7):727-736. https://doi.org/10.1080/10715762.2019.1623883.

[120] Ding MG, Shi R, Fu F, et al. Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. J Adv Res. 2023; 47:151-162. https://doi.org/10.1016/j.jare.2022.07.002.

[121] Yuan L, Yang JC, Li Y, et al.Matrine alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial dysfunction and inflammation via SIRT3/OPA1 pathway. J Cell Mol Med. 2022; 26(13):3702-3715. https://doi.org/10.1111/jcmm.17398.

[122] Hao Y, Liu HM, Wei X, et al. Diallyl trisulfide attenuates hyperglycemia-induced endothelial apoptosis by inhibition of Drp1-mediated mitochondrial fission. Acta Diabetol. 2019; 56(11):1177-1189. https://doi.org/10.1007/s00592-019-01366-.

[123] Wu Q, Chen YY, Wang ZW, et al. Mangiferin inhibits PDGF-BB-induced proliferation and migration of rat vascular smooth muscle cells and alleviates neointimal formation in mice through the AMPK/Drp 1 axis. Oxid Med Cell Longev. 2021; 2021:3119953. https://doi.org/10.1155/2021/3119953.389.

[124] Zhang XL, Huang WM, Tang PC, et al. Anti-inflammatory and neuroprotective effects of natural cordycepin in rotenone-induced PD models through inhibiting Drp1-mediated mitochondrial fission. Neurotoxicology. 2021; 84:1-13. https://doi.org/10.1016/j.neuro.2021.02.002.

[125] Wang LT, He PC, Li AQ, et al. Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics. Acta Pharmacol Sin. 2021; 42(12):2033-2045. https://doi.org/10.1038/s41401-021-00623-6.

[126] Deng XH, Liu JJ, Liu LT, et al. Drp1-mediated mitochondrial fission contributes to baicalein-induced apoptosis and autophagy in lung cancer via activation of AMPK signaling pathway. Int J Biol Sci. 2020; 16(8):1403-1416. https://doi.org/10.7150/ijbs.41768.

[127] Cao Jy, Ma Xy, Yan Xx, et al. Kaempferol induces mitochondrial dysfunction and mitophagy by activating the LKB1/AMPK/MFF pathway in breast precancerous lesions. Phytother Res. 2023; 37(8):3602-3616. https://doi.org/10.1002/ptr.7838.

[128] Chen W, Wang N, Li RC, et al. Salvianolic acid B renders glioma cells more sensitive to radiation via Fis-1-mediated mitochondrial dysfunction. Biomed Pharmacother. 2018; 107:1230-1236. https://doi.org/10.1016/j.biopha.2018.08.113.

[129] Farrand L, Byun S, Kim JY, et al. Piceatannol enhances cisplatin sensitivity in ovarian cancer via modulation of p53, X-linked inhibitor of apoptosis protein (XIAP), and mitochondrial fission. J Biol Chem. 2013; 288(33):23740-23750. https://doi.org/10.1074/jbc.M113.487686.

[130] Zhang YN, Liu SZ, Cao D, et al. Rg1 improves Alzheimer’s disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway. J Ethnopharmacol. 2025; 340:119285. https://doi.org/10.1016/j.jep.2024.119285.

[131] Li SS, Sun XX, Xu LX, et al. Baicalin attenuates in vivo and in vitro hyperglycemia-exacerbated ischemia/reperfusion injury by regulating mitochondrial function in a manner dependent on AMPK. Eur J Pharmacol. 2017; 815:118-126. https://doi.org/10.1016/j.ejphar.2017.07.041.

[132] Pereira CS, Teixeira MH, Russell DA, et al. Mechanism of rotenone binding to respiratory complex I depends on ligand flexibility. Sci Rep. 2023; 13(1):6738. https://doi.org/10.1038/s41598-023-33333-6.

[133] Wang XK, Li H, Li JR, et al. Berberine dissociates mitochondrial complex I by SIRT3-dependent deacetylation of NDUFS1 to improve hepatocellular glucose and lipid metabolism. Sci China Life Sci. 2025; 68(9):2676-2696. https://doi.org/10.1007/s11427-024-2834-8.432.

[134] Min HY, Jang HJ, Park KH, et al. The natural compound gracillin exerts potent antitumor activity by targeting mitochondrial complex II. Cell Death Dis. 2019; 10(11):810. https://doi.org/10.1038/s41419-019-2041-.

[135] Zhou L, Jiang LF, Xu ML, et al. Miltirone exhibits antileukemic activity by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways. Sci Rep. 2016; 6:20585. https://doi.org/10.1038/srep20585.

[136] Chiu YH, Chou WL, Ko MC, et al. Curcumin mitigates obesity-driven dysbiosis and liver steatosis while promoting browning and thermogenesis in white adipose tissue of high-fat diet-fed mice. J Nutr Biochem. 2025; 143:109920. https://doi.org/10.1016/j.jnutbio.2025.109920.

[137] Tanaka E, Mitani T, Nakashima M, et al. Theobromine enhances the conversion of white adipocytes into beige adipocytes in a PPARγ activation-dependent manner. J Nutr Biochem. 2022; 100:108898. https://doi.org/10.1016/j.jnutbio.2021.108898.

[138] Xu P, Zhou WJ, Wang S, et al. Alisol A ameliorates vascular cognitive impairment via AMPK/NAMPT/SIRT1-mediated regulation of cholesterol and autophagy. Theranostics. 2025; 15(18):9415-9446. https://doi.org/10.7150/thno.112661.

[139] Hoang T, Kuljanin M, Smith MD, et al. A biophysical study on molecular physiology of the uncoupling proteins of the central nervous system. Biosci Rep. 2015; 35(4):e00226. https://doi.org/10.1042/BSR20150130.

[140] Liu HC, Zhang XJ, Du YY, et al. Leonurine protects brain injury by increased activities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA and Bax, and ameliorated ultrastructure of mitochondria in experimental stroke. Brain Res. 2012; 1474:73-81. https://doi.org/10.1016/j.brainres.2012.07.028.

[141] Chang HY, Huang TC, Chen NN, et al. Combination therapy targeting ectopic ATP synthase and 26S proteasome induces ER stress in breast cancer cells. Cell Death Dis. 2014; 5(11):e1540. https://doi.org/10.1038/cddis.2014.504.

[142] Salomon AR, Voehringer DW, Herzenberg LA, et al. Understanding and exploiting the mechanistic basis for selectivity of polyketide inhibitors of F₀F₁-ATPase. Proc Natl Acad Sci USA. 2000; 97(26):14766-14771. https://doi.org/10.1073/pnas.97.26.14766.

[143] Huang TC, Chang HY, Hsu CH, et al. Targeting therapy for breast carcinoma by ATP synthase inhibitor aurovertin B. J Proteome Res. 2008; 7(4):1433-1444. https://doi.org/10.1021/pr700742.

[144] Mattos DR, Wan X, Serrill JD, et al. The marine-derived macrolactone mandelalide A is an indirect activator of AMPK. Mar Drugs. 2022; 20(7):418. https://doi.org/10.3390/md20070418.

[145] Dou XZ, Guo H, D'Amico T, et al. CryoEM structure with ATP synthase enables late-stage diversification of cruentaren A. Chemistry. 2023; 29(29):e202300262. https://doi.org/10.1002/chem.202300262.

[146] Gledhill JR, Montgomery MG, Leslie AG, et al. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci USA. 2007; 104(34):13632-13637. https://doi.org/10.1073/pnas.0706290104.

[147] Zheng J, Ramirez VD. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol. 2000; 130(5):1115-1123. https://doi.org/10.1038/sj.bjp.0703397.

[148] Reboul E, Thap S, Tourniaire F, et al. Differential effect of dietary antioxidant classes (carotenoids, polyphenols, vitamins C and E) on lutein absorption. Br J Nutr. 2007; 97(3):440-446. https://doi.org/10.1017/S0007114507352604.

[149] Mohd Zaffarin AS, Ng SF, Ng MH, et al. Pharmacology and pharmacokinetics of vitamin E: nanoformulations to enhance bioavailability. Int J Nanomedicine. 2020; 15:9961-9974. https://doi.org/10.2147/IJN.S276355.

[150] Qiao JP, Kong XY, Kong AY, et al. Pharmacokinetics and biotransformation of tea polyphenols. Curr Drug Metab. 2014; 15(1):30-36. https://doi.org/10.2174/1389200214666131229111336.

[151] McLaren DS, Kraemer K. Bioavailability of carotenoids. World Rev Nutr Diet. 2012; 103:27-32. https://doi.org/10.1159/000171008.

[152] Chang X, Zhou SY, Yan ZQ, et al. Potential candidates of natural antioxidants from herbs for treating lung disorders: focus on redox balance and natural products. Phytother Res. 2025; 39(8):3353-3385. https://doi.org/10.1002/ptr.70008.

[153] Shen Q, Fang J, Guo HJ, et al. Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease. Free Radic Biol Med. 2023; 203:45-57. https://doi.org/10.1016/j.freeradbiomed.2023.03.022.

[154] Lu YW, Hao RJ, Wei YY, et al. The protective effect of harpagoside on angiotensin II (Ang II)-induced blood-brain barrier leakage in vitro. Phytother Res. 2021; 35(11):6241-6254. https://doi.org/10.1002/ptr.7269.

[155] Li HT, Tan F, Zhang TH, et al. Peroxiredoxin 6 mediates the protective function of curcumin pretreatment in acute lung injury induced by serum from patients undergoing one-lung ventilation in vitro. BMC Pulm Med. 2022; 22(1):192. https://doi.org/10.1186/s12890-022-01988-.

[156] Gao F, Zhao YC, Zhang B, et al. Orientin alleviates ox-LDL-induced oxidative stress, inflammation and apoptosis in human vascular endothelial cells by regulating Sestrin 1 (SESN1)-mediated autophagy. J Mol Histol. 2024; 55(1):109-120. https://doi.org/10.1007/s10735-023-10176-.

[157] Lv C, Huang Y, Wang Q, et al. Ainsliadimer A induces ROS-mediated apoptosis in colorectal cancer cells via directly targeting peroxiredoxin 1 and 2. Cell Chem Biol. 2023; 30(3):295-307.e5. https://doi.org/10.1016/j.chembiol.2023.02.003.

[158] Zhao BX, Liang ZH, Zhang LS, et al. Ponicidin promotes hepatocellular carcinoma mitochondrial apoptosis by stabilizing Keap1-PGAM5 complex. Adv Sci (Weinh). 2024; 11(38):e2406080. https://doi.org/10.1002/advs.202406080.

[159] Kim SH, Kim KY, Yu SN, et al. Silibinin induces mitochondrial NOX4-mediated endoplasmic reticulum stress response and its subsequent apoptosis. BMC Cancer. 2016; 16:452. https://doi.org/10.1186/s12885-016-2516-6.

[160] Yen GC, Duh PD, Tsai HL, et al. Pro-oxidative properties of flavonoids in human lymphocytes. Biosci Biotechnol Biochem. 2003; 67(6):1215-1222. https://doi.org/10.1271/bbb.67.1215.

[161] Ryu S, Lim W, Bazer FW, et al. Chrysin induces death of prostate cancer cells by inducing ROS and ER stress. J Cell Physiol. 2017; 232(12):3786-3797. https://doi.org/10.1002/jcp.25861.

[162] Wong VK, Li T, Law BY, et al. Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells. Cell Death Dis. 2013; 4(7):e720. https://doi.org/10.1038/cddis.2013.217.

[163] Balakrishnan K, Wierda WG, Keating MJ, et al. Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2008; 112(5):1971-1980. https://doi.org/10.1182/blood-2007-12-126946.

[164] Jacquemin G, Granci V, Gallouet AS, et al. Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin’s lymphoma B cells. Haematologica. 2012; 97(1):38-46. https://doi.org/10.3324/haematol.2011.046466.

[165] Siegel C, Li J, Liu FD, et al. miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci USA. 2011; 108(28):11662-11667. https://doi.org/10.1073/pnas.1102635108

[166] Han QR, Zhang C, Zhang YB, et al. Bufarenogin induces intrinsic apoptosis via Bax and ANT cooperation. Pharmacol Res Perspect. 2021; 9(1):e00694. https://doi.org/10.1002/prp2.694.

[167] Zamzami N, Kroemer G. The mitochondrion in apoptosis: how Pandora’s box opens. Nat Rev Mol Cell Biol. 2001; 2(1):67-71. https://doi.org/10.1038/35048073.

[168] Xu D, Jin JZ, Yu H, et al. Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2. J Exp Clin Cancer Res. 2017; 36(1):44. https://doi.org/10.1186/s13046-017-0514-4.

[169] Misevičienė L, Anusevičius Z, Sarlauskas J, et al. Redox reactions of the FAD-containing apoptosis-inducing factor (AIF) with quinoidal xenobiotics: a mechanistic study. Arch Biochem Biophys. 2011; 512(2):183-189. https://doi.org/10.1016/j.abb.2011.05.015.

[170] Chen Y, Huang JW, Li YM, et al. Bongkrekic acid alleviates airway inflammation via breaking the mPTP/mtDAMPs/RAGE feedback loop in a steroid-insensitive asthma model. Biomed Pharmacother. 2024; 177:117111. https://doi.org/10.1016/j.biopha.2024.117111.

[171] Kim SY, Shim MS, Kim KY, et al. Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death Dis. 2014; 5(3):e1105. https://doi.org/10.1038/cddis.2014.80.

[172] Xiao JL, Wu P, Wang LL, et al. Pubescenoside D ameliorates myocardial ischemia-reperfusion injury via preventing the dissociation of HK2 and promoting mitophagy by targeting GSK-3β. Phytother Res. 2025; 39(3):1578-1591. https://doi.org/10.1002/ptr.8434.

[173] Wang RY, Zhang JY, Wang SW, et al. The cardiotoxicity induced by arsenic trioxide is alleviated by salvianolic acid A via maintaining calcium homeostasis and inhibiting endoplasmic reticulum stress. Molecules. 2019; 24(3):543. https://doi.org/10.3390/molecules24030543.

[174] Hu WJ, Xu TD, Wu P, et al. Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca²⁺-ATPase 2a. Sci Rep. 2017; 7:41017. https://doi.org/10.1038/srep41017.

[175] Wei LL, Yuan YQ, Yang ZT, et al. Ginsenoside Rb1 reduced ischemic stroke-induced apoptosis through endoplasmic reticulum stress-associated IRE1/TRAF2/JNK pathway. Naunyn Schmiedebergs Arch Pharmacol. 2025; 398(1):747-764. https://doi.org/10.1007/s00210-024-03292-4.

[176] Zhang J, Zhu X, Li Y, et al. Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway. J Transl Med. 2025; 23(1):80. https://doi.org/10.1186/s12967-025-06114-0.

[177] Feng TD, Liu YH, Li C, et al. Protective effects of nigranoic acid on cerebral ischemia-reperfusion injury and its mechanism involving apoptotic signaling pathway. Cell Biochem Biophys. 2015; 71(1):345-351. https://doi.org/10.1007/s12013-014-0204-1.

[178] Zheng Q, Liu HH, Zhang H, et al. Ameliorating mitochondrial dysfunction of neurons by biomimetic targeting nanoparticles mediated mitochondrial biogenesis to boost the therapy of Parkinson’s disease. Adv Sci (Weinh). 2023; 10(22):e2300758. https://doi.org/10.1002/advs.202300758.

[179] Pan X, Li Q, Yuan D, et al. Dual-targeted mitophagy activation by curcumin-Zn co-delivery mediates neuroprotection in zebrafish through coordinated PINK1/Parkin and PI3K/AKT/mTOR pathway regulation. Food Res Int. 2025; 221(Pt 3):117464. https://doi.org/10.1016/j.foodres.2025.117464

[180] Liu ZJ, Liu HQ, Xiao C, et al. Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function. J Neurosci Res. 2014; 92(11):1549-1559. https://doi.org/10.1002/jnr.23438.

[181] Lin CB, Wu X. Curcumin protects trabecular meshwork cells from oxidative stress. Invest Ophthalmol Vis Sci. 2016; 57(10):4327-4332. https://doi.org/10.1167/iovs.16-1988.

[182] Stocco B, Toledo K, Salvador M, et al. Dose-dependent effect of resveratrol on bladder cancer cells: chemoprevention and oxidative stress. Maturitas. 2012; 72(1):72-78. https://doi.org/10.1016/j.maturitas.2012.02.004.

[183] Abd el Aziz M, El-Asmer M, Rezq A, et al. Dose-dependent bioavailability indicators for curcumin and two of its novel derivatives. Biofactors. 2014; 40(1):132-137. https://doi.org/10.1002/biof.1118.

[184] Musso G, Pinach S, Mariano F, et al. Effect of phospholipid curcumin Meriva on liver histology and kidney disease in nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled trial. Hepatology. 2025; 81(2):560-575. https://doi.org/10.1097/HEP.0000000000000937.

[185] Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998; 64(4):353-356. https://doi.org/10.1055/s-2006-957450.

[186] Clinicaltrials. gov. Curcumin as a Novel Treatment to Improve Cognitive Dysfunction in Schizophrenia. Accessed 22 September 2025. https://www.clinicaltrials.gov/study/NCT02104752.

[187] Gillessen A, Schmidt HH. Silymarin as supportive treatment in liver diseases: a narrative review. Adv Ther. 2020; 37(4):1279-1301. https://doi.org/10.1007/s12325-020-01251-.

[188] Jazz Pharmaceuticals.Medication Guide EPIDIOLEX® (EH-peh-DYE-oh-lex) (cannabidiol) oral solution. Accessed 22 September 2025. https://www.epidiolex.com/MedGuide.

[189] Song J, He GN, Dai L. A comprehensive review on celastrol, triptolide and triptonide: Insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes. Biomed Pharmacother. 2023; 162:114705. https://doi.org/10.1016/j.biopha.2023.114705.

[190] Gradishar WJ.Albumin-bound paclitaxel: a next-generation taxane. Expert Opin Pharmacother. 2006; 7(8):1041-1053. https://doi.org/10.1517/14656566.7.8.1041.

[191] Lan JR, Zhao YY, Dong FX, et al. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 2015; 161:69-81. https://doi.org/10.1016/j.jep.2014.09.049.

[192] Andersen LP, Gögenur I, Rosenberg J, et al. The safety of melatonin in humans. Clin Drug Invest. 2016; 36(3):169-175. https://doi.org/10.1007/s40261-015-0368-5.

[193] Gangwal A, Lavecchia A. Artificial intelligence in natural product drug discovery: current applications and future perspectives. J Med Chem. 2025; 68(4):3948-3969. https://doi.org/10.1021/acs.jmedchem.4c01257.

[194] Zhou C, Gong T, Chen JJ, et al. Production of a novel protopanaxatriol-type ginsenoside by yeast cell factories. Bioengineering (Basel). 2023; 10(4):463. https://doi.org/10.3390/bioengineering10040463.

[195] Wu JJ, Zhou P, Zhang X, et al. Efficient de novo synthesis of resveratrol by metabolically engineered Escherichia coli. J Ind Microbiol Biotechnol. 2017; 44(7):1083-1095. https://doi.org/10.1007/s10295-017-1937-9.

[196] Li X, Liu ZQ, Liao J, et al. Network pharmacology approaches for research of Traditional Chinese Medicines. Chin J Nat Med. 2023; 21(5):323-332. https://doi.org/10.1016/S1875-5364(23)60429-.

[197] Zhang HW, Lv C, Zhang LJ, et al. Application of omics- and multi-omics-based techniques for natural product target discovery. Biomed Pharmacother. 2021; 141:111833. https://doi.org/10.1016/j.biopha.2021.111833.