Research Progress on Types and Mechanisms of Fish-Derived Anti-Inflammatory Peptides

It is estimated that the global annual fish output reached approximately 110 million tons in 2023, 80% of which is for human consumption. Fish products are rich in protein and other nutrients, alongside a variety of functional components. In recent years, fish-derived functional peptides have attracted extensive attention from the food industry and yielded abundant research findings. Bioactive peptides possess promising pharmaceutical potential, as well as great application prospects in cosmetics (anti-aging and antioxidant properties) and food industry (foaming and emulsifying properties). To date, scientists have isolated numerous functional peptides from fish, including anti-inflammatory peptides, antioxidant peptides and antimicrobial peptides.

Anti-inflammatory peptides refer to peptides composed of one or multiple amino acids that regulate the production of inflammatory factors and signaling pathways [1]. They remain biologically inactive within intact protein structures and only exert corresponding biological activities after processing and other treatments [3,4]. Studies have demonstrated that polypeptides derived from eggs, meat, fish and other raw materials exhibit certain anti-inflammatory effects. To facilitate further research on fish-derived anti-inflammatory peptides, this paper systematically summarizes and analyzes relevant studies published over the past decade.

1.Hazards of Inflammation to Human Health

Inflammation is a complex physiological response triggered when the body reacts to external harmful stimuli and infections [6]. Acute inflammation can resolve spontaneously. However, chronic inflammation induces excessive secretion of inflammatory factors and subsequently triggers a series of diseases, which is attributed to the upregulated expression of cytokines, chemokines, nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPK) and Toll-like receptors (TLRs) (Figure 1) [7,8]. Cyclooxygenase-2 (COX2) is a typical inflammatory mediator produced in macrophages upon inflammatory stimulation; arachidonic acid is converted into prostaglandin E2 (PGE2) catalyzed by COX2. Existing research confirms that PGE2 acts as a key mediator of rheumatoid arthritis and osteoarthritis.

NF-κB is a transcription factor found in all nucleated cells that modulates gene expression induced by diverse stress signals, including signal transducer and activator of transcription (STAT), MAPKs, nuclear hormone receptors, pro-inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and COX2. The MAPK signaling pathway participates in a wide range of fundamental cellular processes and integrates diverse signals via covalent phosphorylation of intermediate signaling molecules. The MAPK family consists of p38 kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2). ERK, JNK and p38 can be activated by multiple intracellular and extracellular stimuli such as pro-inflammatory cytokines and oxidative stress.

Reports indicate that up to 20% of human cancers are associated with chronic inflammation caused by viral/bacterial infections, irritant exposure and autoimmune disorders [9]. Multiple anti-inflammatory drugs are available for clinical treatment [10,11], including aspirin and ibuprofen, yet these pharmaceuticals generally carry severe side effects [12], predominantly gastrointestinal irritation, and may even cause irreversible damage to visceral organs in severe cases. Therefore, developing anti-inflammatory agents with low adverse effects is urgently required. Exploring the pathogenesis and influencing factors of inflammation can provide theoretical support for the prevention and treatment of inflammatory diseases.

2. Fish-Derived Anti-Inflammatory Peptides and Their Mechanisms of Action

2.1 Classification of Fish-Derived Anti-Inflammatory Peptides

Fish-derived anti-inflammatory peptides are a class of functional bioactive molecules discovered over the past decade [13], capable of reducing the incidence of inflammatory disorders, preventing cardiovascular diseases and cancers, and supporting brain development and neurological function [14]. These peptides are generally classified according to their distinct anti-inflammatory activities. Researchers have successfully extracted anti-colitis, anti-dermatitis, anti-arthritis and other functional anti-inflammatory peptides from catfish [15], tilapia [16,17], lanternfish [18], monkfish [19] and other aquatic species (Table 1).

In vitro and in vivo experiments have verified the immunomodulatory activity of fish-derived anti-inflammatory peptides. For instance, peptides isolated from catfish and tilapia suppress the secretion of pro-inflammatory mediators including TNF-α, IL-6, IL-1β, IL-8, iNOS, COX2 and PGE2 by inhibiting the MAPK, NF-κB and JAK-STAT signaling cascades. Recent studies have revealed potent bioactivity of sturgeon anti-inflammatory peptides in both cellular and animal models: sturgeon peptides alleviate DSS-induced colitis in mice, increase colon length and reduce the Bacteroidetes/Firmicutes ratio. Additionally, these peptides exert protective effects against oxidative damage in human umbilical vein endothelial cells [20]. Collagen peptides extracted from salmon have also been proven to inhibit the progression of osteoarthritis [21].

2.2 Mechanisms Underlying the Anti-Inflammatory Effects of Fish-Derived Peptides

Fish-derived anti-inflammatory peptides exert bioactivity primarily through suppressing signaling pathways including COX2, NF-κB and MAPK (Figure 2). Peptides bind to cell surface receptors, among which TLRs play a central role in immune responses [23]. When Toll-like receptors recognize toxins on cell membranes, downstream nuclear factors and regulatory molecules are activated to transmit receptor signals and stimulate cells to express antigen-presenting molecules for pathogen elimination. TLR2 and TLR4 are identified as major receptors for anti-inflammatory peptides on RAW264.7 macrophage membranes. TLR activation triggers NF-κB signaling to facilitate RAW264.7 macrophage maturation, accompanied by upregulated release of cytokines and immune-stimulatory molecules. Fish-derived anti-inflammatory peptides are regarded as safe and efficient anti-inflammatory candidates with promising development prospects.

2.2.1 Inhibition of COX2 by Fish-Derived Anti-Inflammatory Peptides

Nonsteroidal anti-inflammatory drugs and selective COX2 inhibitors are widely applied to treat inflammatory disorders by blocking PGE2 secretion, rendering COX2 inhibitors valuable for the functional food industry. Giannetto et al. [24] evaluated the anti-inflammatory capacity of anchovy visceral peptides using RAW264.7 macrophages; the peptides significantly suppressed inflammatory responses, downregulated COX2 expression and prevented IκB-α degradation. Similarly, Saisavoey et al. [25] demonstrated that salmon bone hydrolysate inhibits COX2 mRNA expression in RAW264.7 cells. Chen et al. [26] reported that sea bass skin peptides mitigate LPS-induced upregulation of iNOS and COX2 in BV5 cells.

Elmaidomy et al. [27] verified the inhibitory effect of skin peptides from electric catfish on COX2 expression in arthritic rats. Chen et al. [28] found that sturgeon skin collagen hydrolysate reduces ROS levels in UVB-damaged L929 fibroblasts and suppresses COX2 secretion in zebrafish embryos. Collectively, fish-derived anti-inflammatory peptides alleviate inflammatory reactions by inhibiting COX2 and blocking the conversion of arachidonic acid to PGE2 (Table 2). Nevertheless, COX2 suppression may result from concurrent inhibition of multiple intra- and intercellular inflammatory signaling cascades.

2.2.2 Suppression of the NF-κB Signaling Pathway by Fish-Derived Anti-Inflammatory Peptides

NF-κB is a vital intracellular transcription factor tightly correlated with inflammatory progression; inhibition of NF-κB signal transduction serves as a feasible strategy to attenuate chronic inflammation. Multiple studies have validated the NF-κB inhibitory activity of fish-derived anti-inflammatory peptides (Table 3). Zhang et al. [29] confirmed that tuna backbone peptides alleviate inflammation in necrotizing enterocolitis mice by scavenging reactive oxygen species (ROS) and attenuating NF-κB activation. Li et al. [30] reported that yellowtail milt hydrolysate relieves colitis in mice via suppressing NF-κB and downstream pro-inflammatory cytokines.

Gao et al. [31] observed that sturgeon muscle peptide fractions markedly reduce the expression of IκBα and NF-κB p65 in LPS-stimulated RAW264.7 macrophages. Chen et al. [32] revealed that Pacific cod gelatin polypeptides suppress inflammation by downregulating NF-κB-mediated pro-inflammatory cytokine production. Yang et al. [33] detected weakened NF-κB-p65 expression in splenocytes of irradiated mice treated with salmon-derived marine oligopeptides.

Dai Lin [34] investigated the protective effects of crucian carp swim bladder hydrolysate against ulcerative colitis in mice. The peptides decreased p-p65 expression, inhibited IκBa phosphorylation and degradation, and exerted anti-inflammatory activity through NF-κB suppression. Wu Chujun [35] studied enzymatic hydrolysates of yellowfin tuna muscle and found that fraction F1 targets TLR2 and TLR4 on RAW264.7 cell membranes, activates IκBa kinase and modulates NF-κB signaling to promote anti-inflammatory cytokine secretion and mediate immune protection.

2.2.3 Inhibition of the MAPK Pathway by Fish-Derived Anti-Inflammatory Peptides

Activation of the MAPK pathway accelerates inflammatory progression and elevates the secretion of pro-inflammatory cytokines. Accumulating evidence has proven the MAPK-inhibitory properties of fish-derived anti-inflammatory peptides (Table 4). Elango et al. [36] extracted collagen peptides from mahi-mahi bones, which facilitate osteogenic differentiation of bone marrow mesenchymal stem cells via the p38 MAPK-dependent Runx2 signaling axis. Song et al. [37] demonstrated that tilapia skin collagen peptides alleviate cisplatin-induced cytotoxicity and oxidative injury in mouse thymic epithelial cells by inhibiting ROS generation and MAPK activity, upregulating anti-apoptotic proteins Bcl-2 and Bcl-xL, and downregulating pro-apoptotic Bax and Bad to block cellular apoptosis.

Subhan et al. [38] illustrated that tilapia scale collagen peptides counteract CoCl2/TNF-α-triggered cytotoxicity and oxidative stress in HaCaT keratinocytes through inhibiting the p38/MAPK pathway and reducing iNOS and Bax expression. Gao et al. [39] reported that sturgeon muscle peptides suppress inflammation in LPS-stimulated RAW264.7 macrophages via downregulating MAPK cascades. Yang et al. [40] found that cod myosin heavy chain-derived peptides inhibit RANKL-induced osteoclastogenesis and bone resorption by blocking MAPK and NF-κB activation, lowering tartrate-resistant acid phosphatase (TRAP) activity and reducing osteoclast regulators c-Fos and NFATc1.

Ren Zhexin [41] explored the immunomodulatory activity of monkfish roe peptides in RAW264.7 macrophages. Increased release of NO and cytokines indicated that monkfish roe peptides regulate immune responses by activating the expression of proteins related to the MAPKs/NF-κB signaling pathway.

2.2.4 Inhibitory Effects of Fish-Derived Anti-Inflammatory Peptides on Pro-Inflammatory Cytokines

Cytokines play pivotal roles in immune and inflammatory responses, classified into pro-inflammatory and anti-inflammatory subtypes. Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) exacerbate pathological conditions, while anti-inflammatory cytokines (IL-4, IL-10, IL-11, IL-13) mitigate inflammation and facilitate tissue repair. Choe et al. [42] evaluated the anti-inflammatory activity of flatfish byproduct hydrolysate, which significantly reduces the secretion of IL-6, IL-1β and TNF-α in LPS-challenged RAW264.7 macrophages.

Wei Liuyi [43] constructed a hyperuricemia mouse model to assess the in vivo efficacy of bullet tuna peptides. The peptides downregulate IL-1β, MCP-1 and TNF-α expression and effectively alleviate renal immune inflammation in hyperuricemic mice. Hu Xuyang et al. [44] conducted proliferation assays on RAW264.7 macrophages and confirmed that spotfin croaker peptides significantly suppress the secretion of pro-inflammatory mediators IL-1β and TNF-α. Additional research demonstrated that cod peptides drastically reduce renal inflammatory cytokine levels in chronic renal failure mice, confirming their renoprotective anti-inflammatory capacity.

2.2.5 Regulation of TLRs by Fish-Derived Anti-Inflammatory Peptides

TLRs are pattern recognition receptors located on cell plasma and endosomal membranes that recognize microbial metabolites from bacteria, viruses and pathogens. TLR ligation initiates intracellular signaling cascades including NF-κB, an inducible transcription factor driving the production of pro-inflammatory mediators such as cytokines, chemokines, COX2 and iNOS.

Chen et al. [45] explored the molecular mechanism underlying wound healing promoted by sea bass peptides in mice. Results showed that sea bass peptides markedly reduce COX2 production, as well as the phosphorylation and nuclear translocation of NF-κB downstream of TLR4 signaling. Peptide treatment also accelerated fibroblast wound closure and upregulated cyclin D1 expression.

Figure 3 summarizes the integrated anti-inflammatory mechanisms of fish-derived peptides elaborated above, including modulation of COX2, NF-κB, MAPK pathways and multiple inflammatory mediators via intercellular signal transduction, providing theoretical support for the prevention and treatment of inflammatory disorders.

3 Discussion

Despite extensive research on fish-derived anti-inflammatory peptides worldwide, several limitations remain regarding their application in inflammatory disease prevention and treatment: (1) Current mechanistic investigations are limited to cellular and animal preclinical models, with a scarcity of clinical trial data [46]. Future research should conduct clinical trials covering diverse inflammatory conditions, lesion severities and age groups to establish comprehensive multi-dimensional datasets, laying a solid theoretical foundation for the development of peptide-based anti-inflammatory pharmaceuticals [47,48]. (2) Fish protein hydrolysates contain complex peptide mixtures [49], with variations in peptide fractions, amino acid sequences and raw material sources altering peptide composition and bioactivity [50].

Existing studies predominantly focus on marine fish-derived anti-inflammatory peptides, while freshwater fish resources remain largely underexplored. Further molecular mechanistic research is required to standardize peptide composition and activity consistency, enabling standardized production of peptide products. Future research should prioritize the preparation of fish anti-inflammatory peptides with defined amino acid profiles for commercial applications in nutraceuticals and cosmeceuticals.

Fish-derived anti-inflammatory peptides possess great potential for developing functional foods and therapeutic agents. Analysis of literature published over the past decade has identified more than 50 types of anti-inflammatory peptides isolated from tuna, salmon, sturgeon, sea bass, cod and other fish species, exhibiting anti-colitis, anti-arthritis, anti-nephritis and anti-dermatitis activities. The core anti-inflammatory mechanism of these peptides relies on suppressing key transcription factor NF-κB, pro-inflammatory cytokines (IL-6), COX2 and MAPK signaling cascades to alleviate inflammatory lesions.

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