How lung tumors hijack an ancient marine metabolic axis to promote malignant growth

by Zhang Nannan, Chinese Academy of Sciences

edited by Sadie Harley, reviewed by Robert Egan

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Researchers at the Institute of Oceanology of the Chinese Academy of Sciences (IOCAS) have shown how a metabolic mechanism underlying thermal tolerance in intertidal oysters sheds light on malignant proliferation in human lung adenocarcinoma.

The research, published in PNAS, focuses on how cells regulate glycolysis to maintain energy production under conditions of energy stress.

The IOCAS marine shellfish research team uncovered an ancient energy-sensing signaling cascade, termed the KAT2/HDACIIa–PGK–ALDO axis. The axis orchestrates a sophisticated "dual degradation inhibition" mechanism involving the key glycolytic enzymes phosphoglycerate kinase (PGK) and aldolase (ALDO). This mechanism stabilizes and hyperactivates both enzymes to meet cellular energy demands.

A two-pronged glycolysis safeguard

Integrating multi-omics data, gene editing and biochemical functional assays, the researchers discovered that under energy stress, the balance between the acetyltransferase KAT2 and the deacetylase HDACIIa shifts to promote the acetylation of PGK. This modification shields PGK from ubiquitin-proteasomal degradation while strengthening its interaction with ALDO.

In turn, stabilized PGK exhibits a noncanonical protein kinase activity that directly phosphorylates ALDO, simultaneously boosting its catalytic efficiency and suppressing its chaperone-mediated autophagic-lysosomal degradation (CMA).

By concurrently shutting down both proteasomal and CMA-mediated lysosomal degradation, this cascade achieves a potent "stabilization-plus-activation" effect, thereby amplifying glycolytic flux to ensure cell survival.

From oyster stress to tumor growth

The researchers then identified a striking metabolic parallel between intertidal oysters and human tumors. Sessile intertidal oysters, which regularly endure severe heat, aerial exposure and hypoxia, exhibit metabolic reprogramming toward aerobic glycolysis that closely mirrors the "Warburg effect" in human tumors.

Building on this evolutionary parallel, the team demonstrated that human lung cancer cells "hijack" this ancient stress-response axis—upregulating KAT2A and downregulating HDAC5 to drive persistent hyperacetylation of PGK1-K75 and hyperphosphorylation of ALDOA-S272, directly fueling malignant proliferation and metastasis.

"The hypoxia and energy crises endured daily by intertidal oysters remarkably mirror the human tumor microenvironment," said Dr. Wang Chaogang, first author of the study. "Their extraordinary metabolic tolerance and adaptability make them a potential unconventional model organism to decipher the fundamental principles of tumor metabolism."

An evolutionary clue for therapy

"Our study bridges marine evolutionary adaptation with human cancer metabolism," said Professor Li Li, corresponding author of the study. "Hundreds of millions of years of evolution in the harsh intertidal environment have endowed oysters with an ingenious metabolic defense system."

This study not only elucidates the thermal adaptation strategies of marine invertebrates in response to climate warming from an evolutionary biology perspective but also unveils promising therapeutic targets for the clinical diagnosis and treatment of human malignancies.

Publication details

Chaogang Wang et al, The KAT2/HDACⅡa–PGK–ALDO axis constitutes a dual degradation inhibition cascade links energy stress to glycolytic amplification, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2533429123

Journal information: Proceedings of the National Academy of Sciences

Key medical concepts

GlycolysisChaperone-Mediated Autophagy

Clinical categories

OncologyPulmonary medicine Provided by Chinese Academy of Sciences Who's behind this story?

Sadie Harley

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