KPV

KPV (Lys–Pro–Val) is a tripeptide derived from α-MSH’s C-terminus that retains potent anti-inflammatory and immunomodulatory effects without pigmentation changes. It supports wound healing, gut health, and has antimicrobial activity.

- Reduce inflammation and support immune function (IBD, skin disorders)

- Promote gut healing and tissue repair

Mechanism of Action

How this peptide works in the body

Inhibition of NF-κB Signaling via IκBα Stabilization and Nuclear Import Blockade

KPV suppresses the canonical NF-κB inflammatory cascade by stabilizing IκBα, the inhibitory protein that sequesters the NF-κB p65/p50 heterodimer in the cytoplasm. Normally, inflammatory stimuli trigger IKK (IκB kinase) activation, phosphorylating IκBα and marking it for ubiquitin-mediated degradation. KPV inhibits this phosphorylation, preserving IκBα and preventing NF-κB activation. It also competes for binding at the nuclear localization sequence (NLS) on the p65 subunit, blocking its interaction with importin-α3 (Imp-α3) and nuclear translocation. This dual mechanism suppresses transcription of pro-inflammatory genes like TNF-α, IL-1β, IL-6, and IL-8.

Melanocortin Receptor 3 (MC3R) Activation and cAMP/PKA Signaling Cascade

As a fragment of α-MSH, KPV selectively activates MC3R on immune and epithelial cells. This receptor is coupled to Gs proteins that stimulate adenylate cyclase, increasing intracellular cAMP. Elevated cAMP activates protein kinase A (PKA), which phosphorylates and inactivates IKKβ, reinforcing NF-κB suppression. PKA also activates CREB, upregulating anti-inflammatory genes such as IL-10 and HO-1, which promote resolution-phase immunity and cellular protection.

Suppression of MAPK Signaling Pathways (JNK/p38 Axis)

KPV reduces activation of the stress-responsive MAPK pathways, specifically JNK (c-Jun N-terminal kinase) and p38 MAPK. These kinases are typically activated downstream of Toll-like receptors (TLRs) and TNF-α signaling. Their phosphorylation leads to enhanced transcription of inflammatory mediators via AP-1 and ATF-2. KPV inhibits this phosphorylation cascade, thereby attenuating gene expression linked to chemotaxis, vascular permeability, and immune cell infiltration.

Inhibition of Matrix Metalloproteinase-9 (MMP-9) Activity

KPV significantly reduces MMP-9 expression and enzymatic activity in epithelial tissues. MMP-9, a zinc-dependent endopeptidase, breaks down type IV collagen in the basement membrane, facilitating immune cell migration but also tissue degradation. KPV suppresses MMP-9 transcription through NF-κB inhibition and possibly via direct AP-1 downregulation. This helps preserve mucosal and dermal integrity, especially under inflammatory stress.

Modulation of Cytokine Production and Immunophenotype

KPV downregulates secretion of TNF-α, IL-6, IL-8, and interferon-gamma (IFN-γ) through upstream NF-κB and MAPK blockade. Concurrently, it enhances production of anti-inflammatory cytokines such as IL-10 and TGF-β1. This shift facilitates the transition of macrophages from M1 (pro-inflammatory) to M2 (tissue-repairing) phenotypes, promoting immune tolerance and tissue regeneration.

Targeted Uptake via PepT1-Mediated Transport

KPV is efficiently transported into epithelial cells via the proton-coupled oligopeptide transporter PepT1, which is highly expressed in the small intestine and upregulated during inflammation. This allows for selective accumulation of KPV in inflamed intestinal tissues, enhancing its therapeutic effect in colitis and related diseases while minimizing systemic exposure.