Smoking causes serious diseases such as lung cancer, cardiovascular disease and chronic obstructive diseases. Undoubtedly, the best way for smokers to prevent the adverse health effects of tobacco is to quit smoking. Over the last years, tobacco harm reduction has also emerged as a policy that can complement traditional tobacco control intervention such as prevention and cessation.Here we show results of a 90-day rat inhalation study that was conducted in accordance with Organization for Economic Co-operation and Development (OECD) test guidance 413 to characterize potential adverse effects, caused by subchronic exposure to the tobacco heating system (THS) 2.2 aerosol, a heat-not-burn tobacco product, and to compare with those induced by the smoke generated from the reference cigarette 3R4F. In addition, a systems toxicology approach with additional animals was included to further characterize the exposure effects on the transcriptome and proteome of the lung, also referred to a OECD (+).THS 2.2 consists of three distinct components: (i) an electrically heated tobacco product (EHTP), with unique processed tobacco made from tobacco powder, (ii) a holder into which the EHTP is inserted and which heats the tobacco material by means of an electronically controlled heater, and (iii) a charger that is used to recharge the holder after each use. The holder heats the EHTP at a temperature not exceeding 350°C.