TMED9 Promotes NSCLC Progression by Stabilizing ATG9A Through USP5-Mediated Deubiquitination and Activating Autophagy

This study demonstrates that TMED9 is overexpressed in non-small cell lung cancer (NSCLC) and, using multiple independent sample cohorts, shows that its expression level is significantly associated with poor patient prognosis.

Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer and is characterized by strong invasiveness and high mortality. Despite its major clinical significance, the molecular mechanisms driving its initiation and progression remain incompletely understood.

Chen Minbin and Na Liu from Jiangsu University published a research article entitled “TMED9 drives non-small-cell lung cancer progression via promotion of autophagy by recruiting USP5 to deubiquitinate ATG9A” online in PNAS. The study showed that TMED9 is overexpressed in NSCLC, and analysis across multiple independent datasets revealed that elevated TMED9 expression is significantly correlated with unfavorable clinical outcomes.

Gain-of-function and loss-of-function experiments further demonstrated that TMED9 promotes NSCLC cell proliferation, invasion, and migration in vitro, and significantly accelerates tumor growth and metastasis in vivo.

Mechanistically, TMED9 interacts with ATG9A and recruits the deubiquitinase USP5, thereby promoting the deubiquitination and stabilization of ATG9A, which in turn activates autophagy and drives malignant progression. Notably, genetic knockout of TMED9 enhances the sensitivity of NSCLC cells to osimertinib.

Overall, these findings identify the TMED9–USP5–ATG9A signaling axis as a key driver of malignant progression in NSCLC and highlight TMED9 as a promising therapeutic target.

Background: NSCLC Remains a Major Clinical Challenge

NSCLC is the most common type of malignancy worldwide and a leading cause of cancer-related death. In recent years, the introduction of targeted therapy and immunotherapy has led to significant progress in NSCLC treatment, with both approaches notably improving patient survival outcomes.

However, treatment options for patients with advanced NSCLC remain limited, and the overall survival rate is still far from satisfactory. Therefore, identifying the key drivers of NSCLC development and progression has become a major research priority and may guide the development of new therapeutic strategies.

Our Featured Proteins

Cat.No. #	Product Name	Source (Host)	Species	Tag	Protein Length	Price
TMED9-642H	Recombinant Human TMED9 Protein, Fc-tagged	HEK293	Human	Fc	1-202 a.a.	Inquiry
TMED9-643H	Recombinant Human TMED9 Protein, His-tagged	HEK293	Human	His	1-202 a.a.	Inquiry
TMED9-1208H	Recombinant Human TMED9 Protein (40-197 aa), GST-tagged	E.coli	Human	GST	40-197 aa	Inquiry
ATG9A-6894H	Recombinant Human ATG9A Protein, Myc/DDK-tagged	HEK293	Human	DDK&Myc		Inquiry
ATG9A-8786H	Recombinant Human ATG9A protein, GST-tagged	E.coli	Human	GST	427-528 aa	Inquiry
ATG9A-8787H	Recombinant Human ATG9A protein, His-tagged	E.coli	Human	His	427-528 aa	Inquiry
USP5-1182H	Recombinant Human USP5 protein, His-tagged	Insect Cells	Human	His	1-835 aa	$498 / 50 µg
USP5-3633H	Recombinant Human USP5, GST-tagged	E.coli	Human	GST	1-300	$319 / 25μg
USP5-158H	Active Recombinant Human USP5 protein, His-tagged	E.coli	Human	His	1-858 a.a.	Inquiry

TMED9 and Its Potential Role in Cancer

Transmembrane emp24 domain-containing protein 9 (TMED9), also known as GP25L2 or GMP25, is a member of the p24/transmembrane emp24 domain-containing protein family. TMED9 primarily mediates vesicular transport in the early secretory pathway and contributes to the structural organization of the endoplasmic reticulum–Golgi intermediate compartment and the Golgi apparatus.

Emerging evidence has shown that TMED9 is aberrantly upregulated in multiple malignancies, including:

hepatocellular carcinoma,
colorectal cancer,
glioblastoma.

In these cancers, TMED9 has been reported to promote tumor progression. However, its expression pattern, functional significance, and underlying molecular mechanisms in NSCLC have remained unclear.

Fig 1. Schematic model showing how TMED9 regulates autophagy and malignant progression in NSCLC (adapted from PNAS)

Autophagy in Cancer Progression and Therapy Resistance

Macroautophagy (commonly referred to as autophagy) is an evolutionarily conserved intracellular degradation process. It involves the formation of double-membrane autophagosomes, which engulf damaged organelles, misfolded proteins, or pathogens and deliver them to lysosomes for degradation and recycling.

Autophagy is essential for maintaining:

cellular homeostasis,
energy metabolic balance,
adaptation to stress.

It is also associated with a wide range of physiological and pathological processes, including cancer development.

Under stress conditions such as nutrient deprivation, autophagy can provide nutrients and energy to tumor cells, thereby promoting their survival and proliferation in hostile microenvironments. In addition, autophagy mediates resistance of cancer cells to anticancer therapies, including chemotherapy and radiotherapy, through multiple molecular mechanisms.

Therefore, modulating autophagy in cancer cells may enhance the efficacy of existing treatment strategies and help reverse therapy resistance. However, the inherent complexity of the autophagy regulatory network remains a major challenge in cancer therapy.

In NSCLC in particular, the precise regulatory mechanisms and functional roles of autophagy have not yet been fully elucidated. A deeper understanding of these pathways is critical for developing innovative therapeutic strategies that can effectively complement current treatment modalities.

Study Conclusion

In this study, the authors identified TMED9 as a key driver of malignant progression in NSCLC. Mechanistic investigations showed that TMED9 regulates autophagy by recruiting the deubiquitinase USP5, which mediates the deubiquitination of the autophagy-related protein ATG9A.

Taken together, these findings establish TMED9 as a potential prognostic biomarker and promising therapeutic target for NSCLC.

Reference

Liu, N., Han, G., Zhang, F., Gu, Q., Liu, Y., Jia, J., Zhu, X., & Chen, M. (2026). TMED9 drives non-small-cell lung cancer progression via promotion of autophagy by recruiting USP5 to deubiquitinate ATG9A. Proceedings of the National Academy of Sciences, 123(27), e2532259123. https://doi.org/10.1073/pnas.2532259123