Honokiol (3,5-di-[2-propenyl]-1,1-biphenyl-2,2-diol), also known as HNK, is a vital bioactive biphenolic compound extracted from the root, stem, or branch bark of Magnolia officinalis. It exhibits a wide range of pharmacological activities including anti-cancer [[1], [2], [3]], anti-anxiety [[4], [5], [6], [7]], anti-inflammatory [[8], [9], [10], [11]], anti-oxygen [[12], [13], [14]], anti-microbial (antibacterial, anti-fungal and anti-viruses) [[15], [16], [17], [18], [19], [20]], neuroprotective [5,21,22], cardiovascular protective effects (antiarrhythmic, anti-thrombotic) [12,[23], [24], [25]]. Both in vitro and in vivo studies have demonstrated its exceptional pharmacological properties in terms of anti-inflammation, neuroprotection, anticancer activity, and antimicrobial effects.

Mitochondrial bioenergetics is a crucial target in the action of HNK [14,26,27]. Mitochondrial dysfunction plays a significant role in numerous chronic diseases, including neurodegenerative diseases (such as Alzheimer's disease, and Parkinson's disease), cardiovascular diseases, diabetes, metabolic syndrome, autoimmune diseases, cancer, and so on [[28], [29], [30], [31]]. Studies have demonstrated that HNK could induce apoptosis of cancer cells by disrupting mitochondrial function and respiration [2,[32], [33], [34]]. Furthermore, mitochondrial dysfunction also contributes to the antimicrobial activity of HNK. It can lead to the overproduction of reactive oxygen species (ROS), disruption of the mitochondrial membrane potential, and inhibition of respiratory function in some fungal pathogens, ultimately resulting in the cessation of cell viability [19,35,36]. Moreover, mitochondrial function is also involved in the treatment of Alzheimer's Disease (AD) with HNK [5]. By increasing SIRT3 levels and preventing oxidative stress, HNK can mitigate apoptosis by preserving mitochondrial integrity and function. Therefore, targeting mitochondrial bioenergetics may be a promising therapeutic approach for developing HNK for clinical use. For example, Ma et al. developed mitochondria-targeted honokiol (Mito-HNK) by conjugating HNK with a compound that facilitates its entry into mitochondria. The Mito-HNK exhibited enhanced antitumor efficacy and potency compared to HNK alone, with no associated toxicity. Mitochondrial targeting groups, such as triphenylphosphine and berberine, were introduced to obtain numerous derivatives from HNK, many of which exhibited excellent anti-tumor effects [[37], [38], [39], [40]].

Moreover, multiple molecular targets are involved in the pharmacological activity of HNK, such as the suppression of various chemokines, enzymes, cell surface adhesion molecules, and protein tyrosine kinase activity. For anti-cancer activity, HNK exhibits a significant effect on anti-apoptotic proteins, cyclin-dependent kinase, upregulation of pro-apoptotic factors and cell cycle suppressors, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), and signal transducers and activators of transcription 3 (STAT3) [14,21,[41], [42], [43]]. HNK could also exhibit anti-microbiota activity by inhibiting biofilm formation and detaching existing biofilms [44]. Exploring HNK and its molecular targets of action may facilitate the development of new drugs. Thus, we will summarize recent studies that describe the molecular mechanisms of action.

In addition, the properties of HNK, including low water solubility, low bioavailability, and easy oxidation, have limited its further study and clinical application. Thus, a great number of scientists have tried to enhance its selectivity and efficacy [45,46]. These researchers modified the structure, synthesized a series of derivatives of simple phenol, examined the pharmacological activity, and obtained a wealth of information on structure-activity relationships (SAR). As a unique pharmacophore structure of HNK, the hydroxylated biphenyl structure plays an important role in biological activity by activating various interactions with the surface of proteins [47,48]. Accumulating evidence has shown that the main structural modification sites of HNK are the phenolic hydroxyl group, benzene ring, and allyl group.

In this review, we will summarize recent advances in HNK analogs and derivatives, and present the structure-activity relationship (SAR) of HNK derivatives. It is hoped that this review will assist researchers in conducting systematic and further studies on HNK derivatives, developing new effective candidates, and expediting their clinical implementation.