The most widely studied pharmacological effect of lucidenic acids is their anti-cancer effect. Lucidenic acids can induce cytotoxicity in different cancer cell lines, including prostate cancer ^[1][54], leukemia ^[2][3][4][11,55,56], liver cancer ^[5][71], and lung cancer cells ^[6][43]. Lucidenic acid A decreased the viability of PC-3 prostatic cancer cells with an IC₅₀ of 35.0 ± 4.1 μM ^[1][54]. Additionally, lucidenic acid A decreased the viability of HL-60 leukemia cells with an IC₅₀ of 61 μM ^[7][57] and 142 μM ^[3][55] after incubation for 72 and 24 h, respectively. Furthermore, treatment with lucidenic acid A for 72 h induced cytotoxic effects in COLO205 colon cancer, HCT-116 colon cancer, and HepG2 hepatoma cells, with IC₅₀ values of 154, 428, and 183 μM, respectively ^[7][57]. Both lucidenic acids A and N exhibited cytotoxicity against KB epidermal carcinoma and P388 leukemia cells ^[7][8][46,57]. Lucidenic acid B induced cytotoxicity in COLO205, HepG2, HL-60, and HT-29 cancer cells ^[7][57]. Among these cells, HL-60 and HepG2 cell lines were the most sensitive to lucidenic acid B, with an IC₅₀ of 45.0 and 112 μM, respectively ^[7][57]. Lucidenic acid C also induced cytotoxic effects in COLO205, HepG2, and HL-60 cancer cell lines, but was not as potent as lucidenic acids A and B ^[7][57]. Lucidenic acid N also exhibited cytotoxic effects against COLO205, HepG2, and HL-60 cells, with an IC₅₀ of 486, 230, and 64.5 μM, respectively ^[7][57].

The mechanism of the cytotoxic action of lucidenic acids has rarely been studied; however, lucidenic acid B has been demonstrated to induce cancer cell apoptosis via the activation of caspase-9 and caspase-3, followed by PARP cleavage ^[2][3][11,55]. The cytotoxic effects of lucidenic acids are also related to G1 phase cell cycle arrest ^[2][4][11,56]. Moreover, eukaryotic DNA polymerases can be inhibited by lucidenic acid O ^[9][49].

Apart from their direct cytotoxic effects, lucidenic acids also possess anti-proliferative properties. Lucidenic acid C exhibited moderate inhibitory activity against A549 human lung adenocarcinoma cell proliferation, with an IC₅₀ between 52.6 and 84.7 μM ^[6][43]. The potential ability of lucidenic acid D to inhibit HepG2 cell proliferation has also been demonstrated based on the chemometric analysis of the spectrum–effect relationship of Ganoderma extracts ^[10][66].

In addition to their cytotoxic and anti-proliferative effects, lucidenic acids can inhibit cancer cell invasion, implying that they may have a potential anti-metastatic effect. For instance, 24 h incubation with 50 µM of lucidenic acids A, B, C, and N inhibited HepG2 cell invasion without affecting cell viability ^[11][58]. The mechanism of action of this anti-invasive effect remains unknown, but it may be associated with the inhibition of matrix metallopeptidase 9 (MMP-9). Lucidenic acid B has been reported to reverse phorbol myristate acetate-induced MMP-9 activity in a dose-response manner [12]. This effect is related to the suppression of both MAPK/ERK1/2 phosphorylation and IκBα protein activation while enhancing the expression of IκBα protein, leading to a decrease in NF-κB DNA-binding activity [12].

Another promising property of lucidenic acids is that certain lucidenic acids, such as lucidenic acids A, E, and N, may potentiate the anti-cancer effect of doxorubicin ^[13][59]. This synergistic effect may be beneficial, as it may lower the dosage required, and hence reduce the adverse drug reactions, such as cardiotoxicity, of doxorubicin. Lucidenic acids are considered to be safe because their cytotoxic and antiproliferative effects are specific to cancer cells. A study showed that lucidenic acid killed 50% of HL-60 leukemia cells at concentrations ranging from 19.3 to 64.5 μM and had no significant effect on the viability of normal peripheral blood lymphocytes ^[2][11].

The target binding sites of lucidenic acids in cancer cells remain unidentified. Computational molecular docking models have demonstrated promising binding energies of lucidenic acids for the Mdm2 receptor (predicted hydrogen bonding with Val93, Ile19, Gln24, Gln18 and His96) and zinc finger 439 protein (predicted hydrogen bonding with at Ser86), suggesting that they may be the target sites of lucidenic acids in breast cancer ^[14][15][72,73]. Mdm2 is a potent inhibitor of the p53 family of transcription factors and tumor suppressors. The function of the zinc finger 439 protein remains unknown, but it is suggested to be involved in the regulation of gene transcription. Moreover, lucidenic acids may act as potential quadruplex stabilizing ligands and promising inhibitors of Bcl-2 ^[16][17][74,75], which is a well-known apoptosis suppressor.

Inflammation is involved in infectious diseases and chronic disorders, such as arthritis, inflammatory bowel disease, and dermatitis. The anti-inflammatory functions of lucidenic acids have been demonstrated by a previous study, which reported that G. lucidum extracts containing lucidenic acids B, D1, D2, E1, and L attenuated lipopolysaccharide-induced pro-inflammatory cytokine and nitric oxide release and increased the expression levels of inducible nitric oxide synthase and cyclo-oxygenase-2 in RAW264.7 cells ^[18][65]. Similarly, lucidenic acid R suppressed 20% of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells ^[19][51]. Moreover, an in vitro study using a protein denaturation assay demonstrated that lucidenic acid A inhibited inflammation, with an IC₅₀ of 13 μg/mL ^[20][27].

In vivo anti-inflammatory effects of lucidenic acids have also been reported. In a mouse model of 12-O-tetradecanoylphorbol-13-acetate-induced ear skin inflammation, the tropical treatment of lucidenic acids A, D2, E2, and P inhibited skin inflammation with ID₅₀ values of 0.07, 0.11, 0.11, and 0.29 mg/ear, respectively ^[21][60].

The thiobarbituric acid reactive substances assay has demonstrated that G. lucidum extract can suppress oxidative stress in rat liver mitochondria ^[22][16]. Among the different fractions of G. lucidum extract, the fraction with ganoderic acids A, B, C, and D, lucidenic acid B, and ganodermanontriol as major components had the highest protective effect against lipid peroxidation ^[22][16]. Nevertheless, further studies are required to confirm the antioxidant effect of lucidenic acids.

The Epstein–Barr virus is a key risk factor for many malignant diseases, such as nasopharyngeal carcinoma and Burkitt lymphoma. Notably, lucidenic acid A, C, D2, E2, F, and P, methyl lucidenate A, methyl lucidenate E2, methyl lucidenate Q, and 20-hydroxylucidenic acid N inhibited the activation of the Epstein–Barr virus early antigen in Raji cells ^[21][23][50,60]. Human angiotensin-converting enzyme (hACE2) is the key receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into target cells ^[24][76]. While the efficacy of anti-viral medications decreased with the appearance of new SARS-CoV-2 variants ^[25][10], blocking hACE2 may be an effective method to prevent SARS-CoV-2 infection ^[25][10]. The molecular docking results showed that lucidenic acid A has good binding stability to hACE2 (interaction with the amino acid residues Gln96, Asn33 and Lys26) ^[26][61]. In vitro fluorescence resonance energy transfer tests also demonstrated that lucidenic acid A inhibited hACE2 with an IC₅₀ of 2 μmol/mL ^[26][61]. This suggests that lucidenic acids may be useful for the prevention or treatment of COVID-19.

In addition, molecular docking has demonstrated that lucidenic acids A, B, C, and N can bind to matrix metalloproteinase, so their effects on inhibiting the invasion of hepatitis B virus have been proposed ^[27][62]. Moreover, lucidenic acids may have potential effects on the human immunodeficiency virus (HIV). Lucidenic acid O has been reported to inhibit HIV reverse transcriptase with an IC₅₀ of 67 μM ^[9][49]. Moreover, 20-hydroxylucidenic acid N and 20(21)-dehydrolucidenic acid N, which are derivatives of lucidenic acids, exhibited anti-HIV-1 protease activity ^[28][9].

Neurodegenerative diseases have become prevalent, owing to the aging population, affecting more than 55 million people worldwide ^[29][77]. G. lucidum extract that contains lucidenic acids exhibited neuroprotective effects ^[30][13]. Lucidenic acids A and N and methyl lucidenic E2 inhibited acetylcholinesterase with IC₅₀ values of 24.04 ± 3.46, 25.91 ± 0.89, and 17.14 ± 2.88 μM, respectively ^[31][15]. Furthermore, another study reported that lucidenic acid A inhibited acetylcholinesterase, with an IC₅₀ of 54.5 μM ^[32][78]. In addition, lucidenic acid N inhibited butyrylcholinesterase activity, with an IC₅₀ of 188.36 ± 3.05 μM ^[31][15]. Cholinergic neurotransmitters decline in the brains of patients with Alzheimer’s disease. The inhibition of cholinesterase by lucidenic acid may increase acetylcholine levels in the central nervous system, thus enhancing cholinergic transmission ^[33][79].

Lucidenic acids have the potential to treat hyperlipidemia. Lucidenic acid N at a concentration of 80 μM reduced triglyceride accumulation in 3T3-L1 preadipocytes by approximately 30% ^[34][68]. Lucidenic acid N, methyl lucidenate E2, and methyl lucidenate F have been reported to inhibit adipocyte differentiation ^[35][69]. Butyl lucidenate N, a lucidenic acid derivative, inhibited adipogenesis in 3T3-L1 cells by downregulating the gene expression of sterol regulatory element-binding protein-1c, fatty acid synthase, and acetyl-CoA carboxylase ^[36][70]. Furthermore, lucidenic aid A has been proposed as a component that is associated with the anti-hyperlipidemic effect of Fu-Ling-Pi, a traditional Chinese medicine ^[37][63].

β-Hydroxyβ-methylglutaryl-CoA (HMG-CoA) reductase inhibitors are commonly used as lipid-lowering medications. They can reduce cholesterol biosynthesis and regulate lipid metabolism, thus preventing the incidence of mortality in coronary patients ^[38][80]. The results of virtual screening and in silico profiling have demonstrated the potential of lucidenic acids to interact with HMG-CoA reductase ^[39][67]. Additionally, another study has shown that lucidenic acid E can inhibit HMG-CoA reductase, with an IC₅₀ of 42.9 ± 0.9 μM ^[6][43].

A study reported that lucidenic acids E, H, and Q had promising anti-hyperglycemic properties ^[6][43]. Among these, lucidenic acids E and Q inhibited α-glucosidase, with an IC₅₀ of 32.5 and 60.1 μM, respectively ^[6][43]. They could also inhibit maltase, with an IC₅₀ of 16.9 and 51 μM, respectively ^[6][43]. Moreover, lucidenic acid Q showed inhibitory activity against sucrase in rats, with an IC₅₀ of 69.1 μM ^[6][43]. PTP1B inhibitors are promising therapeutic agents for diabetes ^[40][81]. Lucidenic acids H and E exhibited inhibitory activity against PTP1B within a concentration range of 7.6–41.9 μM ^[6][43]. In addition, lucidenic acid Q inhibited aldose reductase, which may be useful for the prevention of diabetic complications, such as neuropathy ^[6][43].

Apart from the aforementioned pharmacological effects, lucidenic acid I, methyl lucidenate E2, and dehydrolucidenic acid N have immunomodulatory activities that enhance recovery from neutropenia, macrophage formation, and macrophage phagocytosis ^[41][14]. In addition, a study has demonstrated that a G. lucidum nanogel, which contains 6.3% lucidenic acid A and 7.3% lucidenic acid H, is effective for the topical treatment of frostbite ^[42][64].