Succinylation: A novel regulatory axis in cholelithiasis-insights from lysine acetyltransferase 2A/adenosine monophosphate-activated protein kinase signaling

Abstract

Cholelithiasis represents a common clinical condition within the digestive tract and continues to pose a substantial global health challenge, largely due to its high rate of recurrence and a scarcity of effective non-surgical interventions. Although protein succinylation has been widely characterized as a post-translational modification, its implications in cholelithiasis pathogenesis had remained poorly defined. A groundbreaking study by Wang et al demonstrates that lysine acetyltransferase 2A-mediated succinylation of adenosine monophosphate-activated protein kinase suppresses cholelithiasis. This work not only provides novel mechanistic insights into cholelithiasis but also establishes succinylation as a promising therapeutic target, thereby addressing a critical knowledge gap in the field.

Key Words: Cholelithiasis; Succinylation; Lysine acetyltransferase 2A; Adenosine monophosphate-activated protein kinase; Protein post-translational modification

Core Tip: While the role of lysine succinylation, a significant post-translational modification, remains largely unexplored in the context of cholelithiasis, this investigation demonstrates that lysine acetyltransferase 2A-mediated succinylation of adenosine monophosphate-activated protein kinase suppresses cholelithiasis through modulation of the adenosine monophosphate-activated protein kinase/sirtuin 1 signaling axis, thereby attenuating inflammatory responses. These findings offer a transformative understanding of cholelithiasis pathogenesis and establish protein succinylation as a promising therapeutic target, effectively addressing a critical research void in this field.

TO THE EDITOR

Cholelithiasis is a prevalent digestive tract disorder in clinical practice[1], affecting approximately 10%-20% of adults worldwide[2]. It remains a substantial global health burden due to its high recurrence rate and the lack of effective therapeutic strategies beyond cholecystectomy. Existing research on cholelithiasis has primarily focused on metabolic dysregulations, such as imbalances in cholesterol metabolism and inflammatory responses within the biliary system. However, the potential role of protein post-translational modifications (PTMs), which are fundamental mechanisms of cellular functional regulation, has long been overlooked in this disease. Among various PTMs, lysine succinylation has recently emerged as a critical regulator of energy metabolism, inflammatory processes, and cell death in pathologies such as cancer and metabolic syndrome[3-5]. Despite its significance, the involvement of succinylation in cholelithiasis remains largely unexplored.

The seminal study demonstrates a pivotal functional link between succinylation and cholelithiasis progression, identifying lysine acetyltransferase 2A (KAT2A)-mediated succinylation of adenosine monophosphate-activated protein kinase (AMPK) as a key regulatory mechanism[6]. These findings not only delineate a novel pathway but also reveal promising therapeutic targets for this prevalent condition. This work makes significant and original contributions to the field. It addresses a critical knowledge gap by providing the first evidence that succinylation plays a functional role in cholelithiasis pathogenesis. While other post-translational modifications, such as acetylation, phosphorylation, and ubiquitination, have been implicated in biliary diseases, succinylation introduces a distinct regulatory dimension due to its profound influence on metabolic enzymes and inflammatory cascades, thereby enriching our mechanistic understanding of gallstone formation. Furthermore, the study identifies KAT2A as a dedicated succinylation regulator and AMPK K170 as a specific functional site, offering a highly precise molecular target for therapeutic development. In contrast to conventional broad-spectrum PTM modulators, which are often limited due to off-target effects, strategies focused on KAT2A or site-specific AMPK succinylation may enable more selective and effective interventions. More importantly, the authors demonstrates that KAT2A-mediated AMPK succinylation significantly increases pyroptosis rate, inflammatory responses, and the expression of pyroptosis-related proteins in gallbladder microenvironmental cells via the AMPK/sirtuin 1 (SIRT1) signaling pathway. This finding establishes a novel link between succinylation and two core pathways in metabolic inflammation, pyroptosis and AMPK/SIRT1 signaling, proposing succinylation as a potential master regulator that integrates metabolic and inflammatory responses in the gallbladder microenvironment.

While this study provides compelling evidence, several important questions remain unresolved. Although KAT2A is highlighted as a key regulator, succinylation is a dynamic process controlled by both succinyltransferases[7] and desuccinylases[8]. It is still unknown whether desuccinylase activity is altered in cholelithiasis, and how these enzymes interact with KAT2A to fine-tune AMPK succinylation warrants further investigation. It should be considered that the murine model employed may not fully recapitulate human cholelithiasis, particularly given known species-specific variations in bile composition and metabolic regulation. Validation in human clinical cohorts or primary tissue samples will be essential to confirm the translational relevance of these findings.

Notwithstanding these open questions, the study represents a substantial advance in our understanding of cholelithiasis pathophysiology. By establishing a novel link between succinylation, the AMPK/SIRT1 pathway, and pyroptosis, it opens promising new avenues for basic research and therapeutic discovery. As the field moves toward personalized management of biliary diseases, integrating mechanistic insights such as these with clinical practice will be crucial. By targeting succinylation to correct metabolic dysfunction-induced protein modifications, translational research aims to restore cellular energy sensing and death control. Translating this “molecular switch” into biomarkers and drugs paves the way for precise anti-inflammatory therapy in cholelithiasis, preventing severe progression. Future focus will be on inhibitor development and validation in disease models.