The global use of New Psychoactive Substances (NPS) has risen markedly in recent years. By the end of 2024, the European Union Drugs Agency (EUDA) had identified around 1000 NPS, including 47 newly detected compounds, 7 of which were synthetic cathinones. Representing the second-largest category of NPS, synthetic cathinones exhibit psychostimulant properties comparable to those of cocaine, amphetamines, and MDMA. The increasing misuse of these substances poses a significant public health risk due to their unclear pharmacology and well-established links to toxicity and fatalities, emphasizing the need for further biological investigation.

Given that synthetic cathinones are frequently consumed orally, this study investigates the impact on the protein profile of human intestinal Caco-2 epithelial cells following exposure to four synthetic cathinones: 3-CIC (3-chloro-N-isopropylcathinone), 4-CIC (4-chloro-N-isopropylcathinone), 3-Cl-TBC (3-chloro-terc-butylcathinone, commonly known as bupropion), and 4-Cl-TBC (4-chloro-terc-butylcathinone).

Preliminary protein analysis of Caco-2 cells exposed to synthetic cathinones revealed a general reduction in total protein content relatively to non-exposed controls, particularly with 3-CIC and 4-CIC. Among these, 3-CIC induced the most pronounced changes in protein expression, however showing an increased expression of proteins predominantly within the 40–50 kDa range.

These findings suggest an upregulation of several proteins, which was never reported. Given the increasing prevalence of synthetic cathinone abuse and the limited understanding of their toxicological profiles, these preliminary results highlight the need for further studies to identify the affected proteins and elucidate the cellular pathways affected by these substances of abuse.