Inflammation is the body's defensive response to stimuli such as toxins and allergens, resulting in redness, swelling, pain, and other localized manifestations [1], [2], [3]. The macrophages, widely dispersed throughout the body, serve a crucial function in controlling the inflammatory response and regulating the pathophysiology of various disorders, including rheumatoid arthritis, type 2 diabetes, atherosclerosis, and cancer [4], [5]. Lipopolysaccharide (LPS) activated macrophages secrete nitric oxide (NO), cyclooxygenase (COX)-2, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) pro-inflammatory mediators as well as pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL1-β) [6], [7]. The excess release of pro-inflammatory cytokines can lead to severe damage to tissues, multiple organ dysfunction, and even death [8], [9], [10]. Therefore, suppressing the overproduction of pro-inflammatory cytokines is a therapeutic approach for treating inflammatory disorders. The available inflammatory medications, such as non-steroidal anti-inflammatory drugs (NSAIDs) and steroidal anti-inflammatory medications, are frequently associated with adverse effects. The prolonged use of these medications is associated with renal toxicity, hepatotoxicity, and gastrointestinal bleeding [11]. Piperine, which is the major secondary metabolite of piper species (P. nigrum and P. longum), has various health benefits and is used in traditional medicine [12], [13]. It has shown a wide range of biological activities, including anti-inflammatory [14], [15], [16], anti-cancer [17], anti-oxidant [18], anti-depressant [19], neurological effects [20], hepatoprotective [21], anti-thyroid [22], anti-rheumatic arthritis [23], [24] anti-diabetic [25], gastroprotective [26], analgesic [27], anti-microbial [28], anti-asthmatic [12], immunomodulatory [29], anti-diarrheal [30], cardioprotective [31], anti-obesity [32], anti-aging [33], and anti-hyperglycemia [34] properties. Piperine has been reported to enhance the absorption and bioavailability of several drugs [35], such as phenytoin [36], resveratrol [37], nevirapine [38], rifampicin [39], ibuprofen [40], indomethacin [41] and nimesulide [42]. Further, it has been showed that piperine significantly attenuated inflammatory cytokines (TNF-α, IL-6, and IL-1β) and LPS induced lung injuries [43]. The hydrolyzed product of piperine i.e. piperic acid, has also exhibited moderate anti-cancer, anti-bacterial [44], [45], anti-malarial [46], anti-hyperlipidemic [47], anti-leishmanial activities [48], anti-oxidant [49], anti-microbial and anti-biofilm activities [50] together with the reduction in paw edema thickness in mice induced by carrageenan [51]. The presence of α,β unsaturated bonds in piperine (PIP) and piperic acid (PA) can cause mammalian cell damage by forming Michael's adduct with DNA bases and glutathione. [52]. In the present study, we aimed to reduce the conjugated double bond in piperine and piperic acid and elucidate the cell viability and anti-inflammatory potency of tetrahydropiperine (THP) and tetrahydropiperic acid (THPA) in LPS-stimulated RAW 264.7cells and in-vivo experimental models. The chemical structure of PIP, THP, PA, and THPA are shown in Fig. 1.