We reported in the previous Crohn’s and Colitis Congress and published in Refs 1 and 2 ,that a segment of 5 aa of a CD44 variant -Methionine, Threonine, Alanine, Aspartic Acid, Valine (MTADV), called 5-MER peptide (5MP), inhibits the inflammation in DSS and TNBS mouse models of IBD, when subcutaneously injected or orally delivered. Similarly, 5MP inhibited the inflammation in mouse models of Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA; Ref 2). As IBD, MS and RA share up-regulation of pathological Serum Amyloid A (SAA) (which fuels chronic inflammations), we predicted and then showed that 5-MP targets and hampers the pathological SAA, thus ameliorating SAA-associated inflammatory diseases by inhibiting the release of pro-inflammatory cytokines from SAA-activated innate-immunity cells. Now we focus on deciphering 5MP mechanism of action. To this end, we show that 1. Rats with Collagen-Induced Arthritis (CIA; the animal model of RA), in contrast to mice or man, do not produce under inflammatory conditions SAA. Therefore, 5MP, in the absence of the SAA target, cannot inhibits the rat CIA, that is almost identical to mouse CIA. This fact supports our prediction that SAA is a 5MP target. 2. SAA binds 5MP, as indicated by mass spectrometry. 3. Polymerized and aggregated forms of SAA are the pathological forms of SAA, generating inflammation and amyloidosis, the last could be a severe complication of Crohn’s (Ref 3). Co-Incubation with 5MP interferes with SAA polymerization and aggregation (Figure 1), providing mechanistic explanation for 5MP therapeutic effect in IBD. 4. Human Fibroblasts, monocytes and Peripheral Blood Mononuclear Cells (PBMCs), stimulated with human SAA, release the pro-inflammatory cytokines IL-6, IL-1β and TNFα. Co-incubation of SAA with 5MP (but not with scrambled peptide TMVAD) suppresses the cytokines release from the cells, providing evidence on the 5-MP potency to interfere with SAA-cytokine destructive cross-talk. In support, mice with IBD reduce inflammation and alleviate IL-6 and IL-1β expression in colonic tissue after 5-MP injection (Figure 2). 5. Normal immune responses, such as DTH or antibody response to foreign antigen, are not inhibited by 5MP. 6. 5-MP is stable in room temperature for at least 5 months. 7. Dogs can tolerate (without signs of harmful effects) 5MP doses, which are much higher than the 5MP therapeutic dose, and finally, a finding which merits a special attention 8. Gene Set Enrichment Analysis reveals that 5-MP activates genes, inducing resistance to IBD, e.g., Batf2, Fgl2, Ifitm3, Pyrin (Nefv), TNFR2 and Tnfrsf9.