UV exposure is critical to skin pigmentation (Al-Sadek and Yusuf, 2024). Studies have demonstrated that UV radiation directly stimulates melanocytes, enhancing their melanin secretion. Specifically, UV irradiation increases the release of melanin-inducing factors such as stem cell factor (SCF), endothelin-1 (ET-1), and Pro-opiomelanocortin (POMC). POMC is enzymatically hydrolyzed into α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone, where α-MSH binding stimulates eumelanin production (Koike and Yamasaki, 2020; Zhang et al., 2024b).

Ultraviolet A (UVA), with a wavelength of 320 nm–400 nm, has the longest wavelengths in the UV spectrum and can easily penetrate skin tissue (Al-Sadek and Yusuf, 2024). UVA’s strong penetration ability and DNA’s weak absorption capacity for UVA can lead to DNA damage through photosensitive reaction (Agar et al., 2004; D'Orazio et al., 2013). Moreover, the absorption of UVA by the skin generates ROS, inducing oxidative stress, which in turn promotes melanosis (Allouche et al., 2021; Bernerd et al., 2022).

Exposure to Ultraviolet B (UVB), known for causing sunburn, is a significant external factor influencing melanin production (Zhang et al., 2024b). Prolonged UVB exposure activates melanocytes, increasing melanin content, which accelerates pigmentation and potentially contributes to various skin disease such as freckles (Azimi et al., 2024).

Pigmentation disorders can result from various factors, including inflammation and genetic inheritance (Hossain et al., 2021; Tearle et al., 2025). Studies have shown that several inflammatory factors are involved in skin pigmentation (Feng et al., 2025). Interleukin-1 (IL-1) a key player in cellular inflammatory responses, and exists in two forms: IL-1α and IL-1β. Keratinocyte growth factor (KGF) facilitates the transport of melanosomes, and when combined with IL-1α, it promotes pigmentation (Cardinali et al., 2005; Chen et al., 2010). IL-1β has been shown to upregulate the expression of tyrosinase and tyrosine-related protein-1 (TRP1), potentially enhancing skin pigmentation by increasing melanin gene expression and promoting the production of additional inflammatory factors (Yang et al., 2022).

IL-4, through the JAK2-STAT6 pathway, reduces MITF and TRP-1 expression in normal human melanocytes (NHM), thereby inhibiting melanin production (Choi et al., 2013). IL-13, which shares similar receptor structures and signaling pathways with IL-4, is also involved in melanogenesis regulation. Epidermal γδ T cells produce both IL-4 and IL-13, with IL-13 being the more abundant cytokine (Renauld, 2001; Nishimura et al., 2008; Kim et al., 2014). Ginsenoside F1 treatment increases IL-13 output from these T cells, contributing to whitening by inhibiting tyrosinase and DCT expression. IL-13 may directly regulate melanogenesis through the JAK2-STAT6 signaling pathway (Han et al., 2014).

While IL-17 alone does not inhibit pigmentation, it significantly amplifies the inhibitory effect of TNF on melanin synthesis through a synergistic interaction (Wang et al., 2013). IL-18 enhances primary human melanocyte growth by inactivating PTEN via the AKT/NF-κB pathway (Zhou et al., 2013; Zhou et al., 2016). IL-33 has been shown to stimulate melanin biosynthesis in NHEM by promoting phosphorylation of p38 MAPK and CREB, leading to increased expression of TYR, TRP-1, and DCT through MITF, ultimately resulting in increased melanin production (Zhou et al., 2014). COX-2 may contribute to the formation of chloasma by activating tyrosinase and melanogenesis-related molecules, therefore promoting melanogenesis (Rodriguez-Arambula et al., 2015).

Gene factors also play a crucial role in inducing pigmentation. For example, differential expression of genes such as SLC24A5 and SLC45A2 influences variations difference in skin color (Soejima and Koda, 2007; Haltaufderhyde and Oancea, 2014).

Amphibians produce various peptides with diverse structures and functions, many of which have been studied for their antibacterial, antioxidant, and skin wound-healing properties (McMillan and Coombs, 2020; Feng G. et al., 2021; Wang X. et al., 2023). Research on Andrias davidianus (Chinese giant salamander) has gained attention due to its high protein content, which can produce a range of bioactive peptides (Chen et al., 2021; Guo et al., 2023). Among these peptides, antioxidants have been extensively studied, with some also exhibiting melanin-inhibiting properties (Speeckaert et al., 2023; Zhan et al., 2024). However, research on the anti-melanin effects of Andrias davidianus remains limited, with more studies focused on Odorrana andersonii.

A study in China in 2023 reported the first findings on OA-VI12, a peptide derived from Odorrana andersonii which regulates melanin synthesis. OA-VI12 was found to inhibit melanin synthesis in B16 cells. At a concentration of 5 μM, the inhibitory effect of OA-VI12 on melanin production was comparable to that of arbutin, but OA-VI12 showed a significantly stronger inhibitory effect at this concentration. OA-VI12 was shown to promote the expression of miR-122-5p while downregulating the expression of MITF and TYR, suggesting that it inhibited melanin synthesis through the miR-122-5p/MITF/TYR axis. Furthermore, OA-VI12 demonstrated transdermal penetration, inhibiting UVB-induced pigmentation in mouse ears and significantly reducing pigmentation (Wang J. et al., 2023).

Subsequently, another melanin-inhibitory peptide from Odorrana andersonii, (Nigrocin-OA27), was identified. Although its molecular weight is twice that of OA-VI12, Nigrocin-OA27 also exhibited a strong transdermal effect. It decreased tyrosinase activity in B16 cells, inhibited melanin synthesis, and interacted with the catalytic site, preventing its binding with L-Dopa, and thereby reducing the enzyme’s catalytic activity (Li J. et al., 2024) (Table 1).

In a 1994 study in Japan, seven cyclic peptides were extracted from the roots of Pseudostellaria heterophylla, all of which exhibited inhibitory activity against mushroom tyrosinase. These peptides were named Pseudostellaria A, B, C, D, E, F, and G (Morita et al., 1994a; Morita et al., 1994b; Morita et al., 1994c). Pseudostellaria C, D and G were found to effectively inhibit melanin synthesis when used to treat melanoma cells cultured in vitro.

Rice protein and rice bran protein hydrolysates are rich in bioactive peptides (Ochiai et al., 2016; Kubglomsong et al., 2018; Zhang et al., 2020). Ruixue Zhang and colleagues used alkaline protease and neutralizing enzymes to hydrolyze rice, and then screened for characteristics, identifying three peptides: LLK, LPK, and PEK. The UVB-induced increase in melanin content and tyrosinase activity was significantly reduced in UVB-irradiated PIG1 cells treated with rice protein hydrolysates. At a 200 μg/mL concentration, both melanin content and tyrosinase activity were lower than those in the positive control group. LLK, LPK, and pEK all reduced melanin content and tyrosinase activity, with PEK exhibiting the strongest inhibitory effect. LLK and pEK downregulated the mRNA expression of TRP-1 and TRP-2 (p < 0.01). These peptides regulate the JNK/β-Trcp/NFκB-p65/MITF signaling pathway at both the mRNA and protein levels to inhibit melanin synthesis (Zhang et al., 2020).

Rice bran protein, a by-product of rice production, has also been explored for its bioactive peptides (Zhang et al., 2024a). Akihito Ochiai isolated three peptides- CT-1, CT-2, and CT-3 from rice bran protein with tyrosinase inhibitory activity. Previous research indicated that TH-10 and P4-peptides with similar sequences-share seven identical amino acid residues. TH-10 contains a tyrosine residue at the N- terminal, whereas P4 has tyrosine residue at the center, N- terminal, and C- terminal. Further analysis of P4 showed that the C-terminal tyrosine residues were the most critical for its tyrosinase inhibitory activity (Shen et al., 2019). CT-1, CT-2, and CT-3 all contained C-terminal tyrosine residues and significantly inhibited tyrosinase activity. CT-1 and CT-3 promoted melanin synthesis in mouse B16 melanoma cells, but CT-2 inhibited melanin synthesis without cytotoxicity (Ochiai et al., 2016). Additionally, researchers found that rice bran albumin exhibited higher tyrosinase inhibitory activity than other protein components. After the hydrolysis of rice bran albumin by papain, 13 peptides were obtained by structural analysis, most of which had characteristics of metal-chelating peptides and tyrosinase inhibitors (Kubglomsong et al., 2018).

Cyclic peptides derived from flaxseed have been proven to possess anti-inflammatory and anticancer properties (Shim et al., 2022; Shim et al., 2024). Recent studies have also demonstrated that a cyclic peptide mixture from flaxseed exhibits tyrosinase inhibitory activity and can inhibit melanin synthesis in B16F10 cells. The proposed mechanism suggests that this effect occurs through the downregulation of the CREB pathway, thereby inhibiting melanin synthesis (Yoon et al., 2023).

Zhiwei Shen and colleagues identified a novel peptide, ECGYF (designated EF-5), from Vigna, which exhibits both tyrosinase inhibitory activity and free radical scavenging ability. In both in vivo and in vitro experiments, EF-5 demonstated a stronger inhibitory effect on tyrosinase than glutathione and arbutin. Molecular docking studies revealed that hydrogen bond and hydrophobic interaction between EF-5 and tyrosinase residues influence tyrosinase activity. It is suggested that EF-5 may induce a conformational change in tyrosinase, which differs from the mechanism of glutathione (Shen et al., 2019).

Feng et al. researched walnuts by hydrolyzing DWMP with alkaline protease and filtering it through an ultrafiltration membrane to obtain DWMPH. The DWMPH was divided into four components based on molecular weight, and the tyrosinase inhibitory activity of each component was evaluated. Interestingly, the results revealed that all four components inhibited both the monophenolase and diphenolase activity of tyrosinase, which had smaller molecular weights, correlating with greater tyrosinase inhibitory activity. Dwmphs-Ⅳ, with the smallest molecular weight, exhibited the highest inhibitory activity, showing ic50 of 3.52 mg/mL and 2.65 mg/mL for monophenolase and diphenolase respectively. Further purification of DWMPHs-Ⅳ yielded three components, with F2 showing the strongest inhibitory effect. Molecular docking studies were performed to assess the binding affinity of these peptides with tyrosinase, where lower scores indicated more stable and reasonable binding. The tripeptide FPY was identified as the most stable compound, with the highest binding affinity. The ic50 values for tyrosinase monophenolase and bisphenolase by FPY were 1.11 mM and 3.20 mm respectively. FPY was found to be a competitive inhibitor of tyrosinase and was not degraded by digestive enzymes (Feng Y.-X. et al., 2021).

Chaenomeles speciosa is known for its anti-tumor, anti-oxidation, and anti-inflammatory effects, but there is limited research on its anti-melanin synthesis properties (Zhang et al., 2010; Xie et al., 2015). In 2020, Deng et al. hydrolyzed and purified papaya seed proteins, obtained two new peptides: NYRRE (F1-a) and RHAKF(F1-b). RHAKF exhibited stronger DPPH radical scavenging ability and lipid peroxidation abilities in antioxidant activity tests. Molecular docking studies revealed more docking sites between RHAKF and tyrosinase, with a closer binding affinity. The IC values for RHAKF and NYRRE were 8.69 mg/mL and 1.15 mg/mL, respectively. RHAKF may possess an imidazole ring capable of metal chelation (Deng et al., 2020) (Table 2).

Melanin plays a protective role in the human body. When ultraviolet rays irradiate the skin, ROS are generated (Chaiprasongsuk and Panich 2022; Yu et al. 2024). Excessive ROS can damage DNA, lipid peroxidation, and cause various issues including cancer (Bickers and Athar 2006; Lee et al., 2021; Chen et al., 2024). Studies have also shown that oxidative stress caused by UV radiation can contribute to hyperpigmentation (Sevilla et al., 2022). Grass Carp Scale Collagen Peptide (FTMGL) demonstrated antioxidant activity similar to kojic acid in B16F10 cells. FTMGL exerts its antioxidant activity by regulating glutathione (GSH) content and enhancing the levels of antioxidant enzymes (SOD, CAT, and GPx), which helps reduce the levels of superoxide dismutase (SOD) and malondialdehyde (MDA)- thus preventing pigment deposition caused by oxidative stress (Hu et al., 2022a). SOD and CAT are key antioxidant enzymes that maintain redox balance within cells (Pudlarz et al., 2020). The direct scavenging of free radicals and the recovery of antioxidant enzyme activity reduced by external stimuli are common antioxidant mechanisms by which peptides inhibit melanin synthesis (Errante et al., 2024).

It is worth mentioning that peptides with strong antioxidant activity often have strong anti-tyrosinase activity. There are abundant hydrophobic amino acids in bioactive peptides, such as Val, Ala, Gly, Iso, Leu, Phe and Pro, which have the ability to scavenge free radicals (Park and Jo, 2019). These amino acids also play an important role in anti-melanin synthesis (Ahuja et al., 2025). At the same time, aromatic amino acids (such as Trp, Leu, Phe, Tyr, Val, Ile) can stabilize active oxygen through direct electron transfer, and Tyr, Phe and Val can significantly enhance TIP's anti-tyrosinase activity (Nie et al., 2017; Shen et al., 2019; Joompang et al., 2020; Thaha et al., 2021; Aizawa and Yamamuro, 2024). Although the antioxidant and anti-melanin production pathways partially overlap, their specific molecular mechanisms have not been fully clarified. It is worth noting that there is still a lack of research on the antioxidant mechanism related to hyperpigmentation induced by environmental factors or endogenous factors (not ultraviolet radiation), which leads to the need to further explore the effectiveness and target of the targeted inhibitory peptide-based hyperpigmentation therapy strategy.

Inflammation can also contribute to hyperpigmentation (Hossain et al., 2021). After treatment with substance P, an undecapeptide, the melanin content and tyrosinase activity were significantly downregulated in B16F10 mouse melanoma cells. Substance P may stimulate the phosphorylation of p70 S6K1 and inhibit the phosphorylation of p38 MAPK by activating the NK-1R receptor, thereby inhibiting TRP1 by MITF, thus playing an anti-melanin synthesis role (Ping et al., 2012). Later studies showed that calcitonin gene-related peptide (CGRP) at 500 ng/mL inhibited tyrosinase activity and melanin synthesis in B16F10 cells in a concentration-dependent manner, especially when combined with substance P (0.1–10 nm). However, CGRP alone did not affect melanin synthesis; its inhibitory effect was mediated by enhancing the expression of NK-1R (Zhou et al., 2015).

In addition to peptides, small molecules can also inhibit abnormal melanin deposition by mediating inflammatory reactions. Asiaticoside (MA) inhibits UV-induced hyperpigmentation by mediating the COX-2 and PGE pathways by inhibiting PAR-2 expression (Jung et al., 2013). Salvianolic acid [CA] has been shown to inhibit melanin deposition in zebrafish skin along with the production and transfer of melanin in skin cells. When CA and LP-GEL were applied together, skin wound healing accelerated, and inflammatory reaction and melanosis were inhibited (Su et al., 2024). Bay 11-7082 inhibits post-inflammatory pigmentation by suppressing inflammation and melanin production (Moon et al. 2025). Solamargine inhibits melanin synthesis in human skin cells induced by UVB by decreasing tyrosinase activity and the expression of MITF, TRP-1, and TRP-2. It also exerts an anti-inflammatory effect by modulating the MAPK/Nrf2/HO-1 signaling pathway (Zhao et al., 2022).

It regulates the transcription of tyrosinase, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2), activates various target genes related to melanin synthesis, and influences the reproduction, proliferation, and survival of melanogenic cells (Wellbrock and Marais, 2005; Cheli et al., 2010; Vachtenheim and Borovansky, 2010). Peptides that inhibit melanin synthesis can modulate MITF expression through various pathways in order to inhibit melanin synthesis.

α-MSH binds to MC1R, which: increases cyclic adenosine monophosphate (cAMP) of the secondary messenger through adenylate cyclase (AC); stimulates protein kinase A(PKA) to translocate and phosphorylate CREB; activates its transcription activity, increases MITF expression, and then activates tyrosinase, promoting melanin synthesis (Pillaiyar et al., 2017). H89 can inhibit this process (Jian et al., 2011). PI3K/AKT/GSK3β pathway regulates melanogenesis by reducing MITF expression. CAMP inhibits PI3K, activates AKT, and increases GSK3β activity. After phosphorylation, it inhibits MITF from binding to a tyrosinase promoter and degrades it (Lee et al., 2021; Zhou et al., 2021). MEK/ERK/MITF Pathway, a negative pathway, and the ERK cascade reaction plays a role in cell growth, which can induce MITF phosphorylation and ubiquitination. The α-MSH trigger signal activates ERK after phosphorylation of MEK by cAMP, and p-ERK promotes MITF degradation and inhibits melanin production (Shirasugi et al., 2010; Huang et al., 2017). P38 MAPK is a member of MAPK, which can up-regulate MITF and tyrosinase. CAMP activates p38 MAPK, phosphorylates CREB and promotes MITF expression (Kang et al., 2020; Choi et al., 2022). SB203580 can interrupt p38 MAPK phosphorylation, and Fargesin inhibits melanin production through this pathway and the MEK/ERK/MITF pathway (Huang et al., 2016; Fu et al., 2019).

In addition to the above channels, there are some channels that are less studied. The zebrafish phosphopeptide Pt5 decreased MITF gene expression through the cAMP signaling pathway, inhibiting melanin synthesis (Liu et al., 2017). Dshp inhibits melanin synthesis by activating ERK and promoting MITF degradation (Choi et al., 2016). Sfrp5pepD disrupts the Wnt/β-catenin signaling pathway by inhibiting the interaction between Axin-1 and β-catenin, affecting the interaction between MITF and β-catenin. This reduces the expression of melanogenic enzymes and ultimately inhibits melanin synthesis (Choi et al., 2024). Additionally, FTMGL not only inhibits the pigment deposition through antioxidant activity, but also reduces MITF expression by modulating p38 and JNK in the cAMP-PI3K/Akt and MAPK signaling pathway, thereby inhibiting melanin synthesis in melanoma cells (Pudlarz et al., 2020) (Figure 2).

Peptides inhibit melanin synthesis, mainly by binding with TRP and MITF in melanin biological process. Molecular docking is a selective method used to help understand the drug-forming screening of small molecules such as peptides and macromolecules (Pinzi and Rastelli, 2019; Festa et al., 2020). This technique is used to predict how peptides bind to related targets that inhibit melanin synthesis, to further study its inhibition mechanism (Paggi et al., 2024).

The catalytic core of tyrosinase is composed of H₂L₂ tetramer, and its active center contains binuclear copper ions, which form a six-coordinated chelating structure through His61, His85, His94(CuA), His259, His263 and His296(CuB) (Baskaran et al., 2021). The redox cycle of Cu²⁺ is the key step to catalyze the oxidation of L-tyrosine to dopaquinone, which depends on the precise regulation of the hydrophobic environment in the active chamber (Bagherzadeh et al., 2015).

CuA and CuB are connected by an oxygen bridge to form a rigid structure, required for catalytic activity. Peptide inhibitors (such as VY-9) occupy hydrophobic pockets (His85, Phe264, etc.) near the cavity entrance, which prevent the substrate L-tyrosine from entering the active cavity and interfere with the coordination between Cu and His residues (such as the chelation of imidazole ring of His85 with Cu), resulting in the loss of enzyme activity (Baskaran et al., 2021; Sepehri et al., 2022; Sangtanoo et al., 2024). Even if the peptide does not directly bind to Cu, covering His residues (such as His259 and His263) will destroy the stable coordination of Cu and reduce its catalytic efficiency (Joompang et al., 2020). The entrance of the active cavity is composed of His85, Met280, Val283 and other residues, and its steric hindrance and π -π stacking (such as Phe264 and benzyl ring of the substrate) jointly determine the substrate selectivity (Yu and Fan, 2021). Short peptides are embedded in hydrophobic cavities in parallel through aromatic rings, enhancing π -π stacking, simulating the binding mode of natural substrates, and blocking the interaction between copper ion and His residues in hydrophobic cavities (Goldfeder et al., 2014).

Peptide inhibitors destroy tyrosinase function through a hydrogen bond network, hydrophobic interaction and electrostatic interaction, and their mechanisms can be divided into two categories: competitive inhibition and non-competitive inhibition. The aromatic amino acids of peptide (tyrosine) form hydrogen bonds with His263, simulating the interaction between phenolic hydroxyl groups of L-tyrosine and His263 (Goldfeder et al., 2014). The hydrophobic residue of the peptide is embedded in the hydrophobic pocket, which enhances the binding stability by van der Waals force and prevents the substrate from sliding into the active cavity (Hu et al., 2022b). Hydrophobic residues (such as Leu and Ala) cover the surface of the active cavity, which reduces the hydrophobic complementarity between the enzyme and the substrate, and further inhibits the catalytic efficiency (Hu et al., 2022b). The charged residues of peptide (such as Arg/Lys) form a salt bridge with the acidic residues on the enzyme surface (Glu256, Asp322), which induces the conformational change of the active center and destroys the stable coordination of copper ion (Deri et al., 2016).

In addition, peptides (such as FRAF) form a multi-level inhibition network by targeting MITF, TYR and TYRP1/2, and its mechanism goes beyond single target intervention: FRAF forms hydrogen bonds with ASP431 and ALA384 of MITF, blocking the combination of MITF and target gene promoters (such as TYR and TYRP1) and inhibiting the expression of melanin synthesis-related enzymes. FRAF binds to PRO20 and GLU19 of TYR through hydrogen bonds, which interferes with its substrate binding pocket. It forms electrostatic interaction with GLU451 of TYRP1 and GLU63 of TYRP2, which destroys its auxiliary function of TYR and inhibits melanin transport and oxidation (Bai et al., 2024) (Table 4; Figure 3).

The results show that the molecular weight, size and amino acid composition of peptide will significantly affect the anti-tyrosinase ability (Putri et al., 2025). Part A in Figure 4 shows that tyrosinase’s inhibitory ability of short peptides is higher than that of long peptides, and the peptides with good water solubility also have higher tyrosinase inhibitory activity. The result of polypeptides is just the opposite, because polypeptides are generally obtained by enzyme hydrolysis. Part B in Figure 4 shows that the cysteine content is as high as 17.66%, significantly higher than other amino acids. The reason for this may be that it can form disulfide bonds with tyrosinase to stabilize the peptide structure, participate in metal ion coordination, and maintain special conformation. The total amount of hydrophobic amino acids, including L (7.98%), I (3.13%) and V (2.85%), is relatively high, which may be related to the fact that they can form a hydrophobic core with tyrosinase or combine with hydrophobic pockets of tyrosinase. Figure 3B can provide some ideas for us to synthesize new tyrosinase inhibitory peptides. Usually, we will choose enzymes with better degrees of hydrolysis, so that the types of long peptides will be scarce, but too few quantities will lead to deviation in statistics. The cysteine content can be as high as 17.5%, which is significantly higher than other amino acids. The reason for this may be that it can form disulfide bonds with tyrosinase to stabilize peptide structure, participate in metal ion coordination and maintain special conformation. The inhibitory potential of peptides on tyrosinase is closely related to its amino acid composition and structural characteristics. For example, the C-terminal tyrosine residue is particularly critical because it significantly promotes tyrosine binding and inhibition by changing the conformation of the enzyme (Kose and Oncel, 2022). Similarly, tetrapeptides containing a N-terminal cysteine can exert tyrosinase inhibition by chelating with copper ions (Joompang et al., 2023). Basic residues (such as arginine) are paired with nonpolar amino acids (such as proline, alanine, valine and leucine), which have a strong inhibitory effect on tyrosinase (Zu et al., 2023). Many peptides exceed the optimal molecular weight threshold (500 Da) for skin penetration, and the partition coefficients (log P) are usually beyond the range required for effective absorption. This limits their ability to penetrate the skin, which will affect tyrosinase inhibition and skin delivery (Mortazavi and Moghimi, 2022). Peptides from fish scale gelatin and egg whites have proved that smaller peptides (400–600 Da) show higher copper ion chelating activity, highlighting the importance of molecular weights in peptide activity (Yap and Gan, 2020; Xue et al., 2022). In addition, studies have shown that the introduction of D-tyrosine into the N-terminal or C-terminal of pentapeptide-18 can reduce the melanin content by 50% at 500 μM, the tyrosinase activity by 18% at the N-terminal and by 25% at the C-terminal. Adding D-tyrosine can endow short functional cosmetic peptides with an anti-melanin effect, which is of great significance to the research of new cosmetics with whitening/anti-inflammatory and whitening/anti-aging functions (Ge et al., 2023).

Cyclization of peptides is a strategy that can make peptides have a more stable conformation, enhancing the stability of enzymatic proteolysis and improving the permeability through biological barriers (Karami et al., 2023). The cyclic peptide Massiliamide obtained from Gram-negative bacterium Massilia albidiflava DSM 17472T has an IC50 of 1.15 μM, and its tyrosinase inhibitory activity exceeds that of kojic acid and arbutin in positive control group (Frediansyah et al., 2021). New delivery systems, including liposomes, nanoparticles, nanoemulsions and microneedles, have been used to improve drug solubility, increase skin permeability or reduce skin irritation, thus enhancing the therapeutic effect (Jing-Yan et al., 2020; D'Souza and Shegokar, 2021; Xing et al., 2021; Saadh et al., 2024). The combination of these technologies and peptides will further increase the therapeutic effect of peptides.