Abstract Chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of mortality worldwide. The causes of COPD are usually determined by multiple factors, among which exposure to cigarette smoke (CS) is the most common cause of COPD. CS exposure has been reported to induce epithelial cell death by apoptosis and necroptosis, and trigger lung inflammation. Most previous studies on cell death focus on the mechanism of apoptosis. Necroptosis, a new form of cell death, has emerged as another important mechanism for COPD pathogenesis. Therefore, revealing a novel target for both apoptosis and necroptosis will help the development of new treatments for COPD. Our preliminary data show that p53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BH3-only Bcl-2 family member, is markedly induced in the lung tissues of COPD patients and mice exposed to CS treatment, as well as in lung epithelial cells treated with air-liquid interface (ALI) CS exposure or cigarette smoking extract (CSE). PUMA deficiency protected against CSE-induced apoptosis and necroptosis in the lung epithelial cells, and mouse alveolar organoids. Depletion of PUMA in the lung epithelial cells also attenuated the macrophage inflammatory profile. Moreover, knockdown of PUMA has higher suppressive effect on pro-inflammatory cytokines induction by CSE exposure than inhibition of cell death, indicating that PUMA might have a new function in triggering inflammation besides cell death. PUMA knock-out mice showed decreased lung inflammation, apoptosis, and necroptosis after 2 months of CS exposure, and rescued lung function loss after 6 months of CS exposure. Based on these preliminary findings, we hypothesize that PUMA mediates CS-induced apoptosis and necroptosis, and contributes to lung inflammation in the pathogenesis of COPD. We further hypothesize that PUMA can be pharmacologically targeted as a novel therapy against COPD. Specifically, we will investigate the functional role of PUMA in CS-induced lung epithelial cell death, as well as inflammatory macrophage activation, and test whether PUMA deletion or inhibition by a first-in-class small molecule inhibitor can protect the lung from CS-induced emphysema. In the proposed studies, we will pursue these three specific aims: (1) Test the hypothesis that PUMA orchestrates CS-induced apoptosis and necroptosis. (2) Test the hypothesis that PUMA induction in lung epithelial cells triggers pro-inflammatory cytokines expression and causes cell death independent lung inflammation. (3) Test the hypothesis that inhibition of PUMA by small molecular weight inhibitors prevents the development of cigarette smoke-induced emphysema in mice. This project is expected to reveal a new function of PUMA in the pathogenesis of COPD, especially its novel function in the induction of inflammatory cytokines. The completion of the proposed studies will provide proof-of- principle evidence for targeting PUMA as a novel therapeutic approach for C...