Curcumin inhibits the activity of ubiquitin ligase Smurf2 to promote NLRP3-dependent pyroptosis in non-small cell lung cancer cells

Sep 23, 2026

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Non-small cell lung cancer (NSCLC) presents major clinical challenges and remains difficult to treat effectively. This study investigates how curcumin affects NSCLC using A549 and NCI-H1299 cells and a mouse xenograft model. Curcumin treatment inhibits cell growth, promotes pyroptosis, and reduces NLRP3 ubiquitination, with NLRP3 knockdown reversing these effects. Smurf2 is shown to interact with NLRP3; Smurf2 modulation alters NLRP3 ubiquitination and pyroptosis, and curcumin directly binds Smurf2 to inhibit its activity. In vivo, curcumin reduces tumor size and shifts pyroptosis markers accordingly, highlighting Smurf2 inhibition as a mechanism.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

Introduction

Curcumin in lung cancer

Pyroptosis and NLRP3 inflammasome

INTERNATIONAL JOURNAL OF ONCOLOGY 66: 21, 2025 Curcumin inhibits the activity of ubiquitin ligase Smurf2 to promote NLRP3‑dependent pyroptosisin non‑small cell lung cancer cells YUNZHU XI 1,2 , SAILI ZENG 1,2 , XIAOWU TAN 1,2 and XIAOYU DENG 1,2 1Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421000, P.R. China; 2Hengyang Medical School, University of South China, Hengyang, Hunan 421000, P.R. China Received September 18, 2024; Accepted January 15, 2025 DOI: 10.3892/ijo.2025.5727 Abstract. Non‑small cell lung cancer (NSCLC) is a malignant tumor of significant clinical relevance. Curcumin has been investigated for its potential anticancer properties, as it has been reported to act through multiple cancer‑related targetsand pathways. The present study aimed to explore the effects of curcumin in NSCLC using both in vitro and in vivo models. NSCLC cell lines (specifically, A549 and NCI‑H1299 cells), and a mouse tumor model established through the subcuta‑ neous injection of A549 cells, were utilized to evaluate the effects of curcumin intervention. The effects of treatment with curcumin on NOD‑like receptor pyrin domain‑containing 3 (NLRP3) ubiquitination, cell pyroptosis and pyroptosis‑asso‑ ciated factors were also evaluated. In addition, Smad ubiquitination regulatory factor 2 (Smurf2) was analyzed via a series of knockdown and overexpression experiments, both in vitro and in vivo, aimed at investigating its association with curcumin and NLRP3. The results obtained from these experi‑ ments showed that curcumin inhibited NSCLC cell growth, promoted pyroptosis and reduced the level of NLRP3 ubiqui‑ tination. NLRP3 knockdown reversed the curcumin‑induced increase in pyroptosis‑associated factors both in vitro and in vivo. Additionally, Smurf2 interacted with NLRP3 and alterations in Smurf2 expression levels influenced NLRP3 ubiquitination and cell pyroptosis . Moreover, molecular docking analysis demonstrated that curcumin could bind directly to Smurf2, which subsequently led to an inhibition of Smurf2 activity. Knockdown of Smurf2 enhanced curcumin's ability to stabilize NLRP3 and to promote pyroptosis, whereas Smurf2 overexpression negated these effects. In the in vivo Correspondence to: Dr Xiaoyu Deng, Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital, University of South China, 30 Jiefang Road, Hengyang, Hunan 421000, P.R. China E‑mail: [13789355762@163.com](13789355762@163.com) Key words: curcumin, smad ubiquitination regulatory factor 2, NOD‑like receptor pyrin domain‑containing 3, pyroptosis, non‑small cell lung cancer animal model, curcumin treatment led to reduced tumor volumes and weights, in addition to a decreased expression level of Ki67 and increased expression levels of NLRP3 and pyroptosis‑associated factors. Similarly, these effects were enhanced or reversed by Smurf2 knockdown or overexpres‑ sion, respectively. In conclusion, the findings of the present study showed that curcumin inhibited Smurf2 activity, thereby promoting NLRP3‑dependent pyroptosis in NSCLC cells. In addition, these findings have provided mechanistic insights into the role of curcumin in NSCLC, opening an avenue for its potential therapeutic application. Introduction Non‑small cell lung cancer (NSCLC) is a prevalent malig‑ nancy that represents a significant global health concern (1) . There were >1.5 million new cases of lung cancer from 2010 to 2017, of which ~85.3% were NSCLC (2). Patients with NSCLC often face challenges that are associated with the limited treat‑ ment options available and poor prognoses, and these severely impact survival outcomes (3) . Despite the advancements that have been made in terms of diagnostic and therapeutic strategies, the overall survival rates for NSCLC remain low at~26.4%(2), due to factors such as drug resistance and adverse treatment effects (4) . Therefore, there is an u

FAQs

What was the main goal of this study on NSCLC?

To determine how curcumin influences NSCLC progression by examining pyroptosis and the roles of NLRP3 and Smurf2 using in vitro and in vivo models.

How does curcumin affect NLRP3 ubiquitination and pyroptosis?

Curcumin inhibits NSCLC cell growth, promotes pyroptosis, and reduces the level of NLRP3 ubiquitination; NLRP3 knockdown reverses the curcumin-induced pyroptosis-associated changes.

What role does Smurf2 play in curcumin-mediated effects?

Smurf2 interacts with NLRP3 and regulates NLRP3 ubiquitination and pyroptosis; curcumin can bind directly to Smurf2, inhibiting Smurf2 activity, while Smurf2 knockdown enhances and Smurf2 overexpression negates curcumin’s effects.

Sep 23, 2026

Uploaded by Aria