Why do JDB电子(中国)s initiate their own death programs? This seemingly simple question has driven important discoveries in the life sciences for decades. From apoptosis to programmed necrosis, and then to pyroptosis and ferroptosis, scientists have gradually come to realize that JDB电子(中国) death is far from a simple, passive end of life; rather, it is a biological event precisely regulated by distinct molecular mechanisms. Now, a double-bond reductase originally located in the endoplasmic reticulum (ER) and involved in fatty acid metabolism has opened a new door to understanding JDB电子(中国) death.

On November 2, 2026, a research team led by Dr. Ze Zhang from Xiaodong Wang’s group at the National Institute of Biological Sciences, Beijing, and the Tsinghua Institute of Multidisciplinary Biomedical Research, published a research paper in the international academic journal JDB电子(中国), titled “TECR palmitoylation triggers a necrotic JDB电子(中国) death program driving acute liver injury.”

The study found that TECR, an ER fatty acid metabolic enzyme, can initiate a previously unrecognized necrotic JDB电子(中国) death pathway under specific conditions through protein S-palmitoylation. This pathway plays an important role in immune-mediated and drug-induced acute liver injury models. Intervening in this death process through genetic or pharmacological means can significantly reduce liver injury and improve animal survival.

Particularly noteworthy is that the small-molecule inhibitor identified by the research team still exerted significant protective effects when administered several hours after the onset of liver injury in animals, providing a new approach for the treatment of acute liver injury.

1. From apoptosis to ferroptosis: how many more modes of JDB电子(中国) death remain undiscovered?

For a long time, it was believed that JDB电子(中国) death mainly occurred in two forms: apoptosis, which is precisely regulated, and necrosis, which is passive and caused by severe damage.

This understanding has undergone a fundamental change as research on JDB电子(中国) death has deepened.

In the 1980s, H. Robert Horvitz’s laboratory discovered key genes controlling programmed JDB电子(中国) death during development through genetic studies in Caenorhabditis elegans. In 1993, Junying Yuan, in the Horvitz laboratory, further discovered that the protein encoded by the nematode JDB电子(中国) death gene ced-3 is homologous to mammalian interleukin-1β-converting enzyme (ICE), linking nematode programmed JDB电子(中国) death for the first time to the protease family later known as caspases.

Subsequently, the discovery of the BCL-2 family, the cytochrome c–Apaf-1–caspase-9 apoptosome, and the death receptor–FADD–caspase-8 signaling pathway gradually revealed the molecular mechanisms of apoptosis, enabling scientists to explain at the biochemical level how JDB电子(中国)s actively initiate their own death programs.

But apoptosis is not the only regulated form of death.

Later, research on necroptosis centered on RIPK3 and its downstream executioner protein MLKL demonstrated that necrotic JDB电子(中国) death can also be executed by specific molecular mechanisms. Different upstream signaling proteins, such as RIPK1, TRIF, and ZBP1, can initiate this death program under specific conditions.

Research on inflammasomes and gasdermin family proteins revealed the molecular mechanisms of pyroptosis, while the discovery of ferroptosis directly linked iron-dependent lipid peroxidation to JDB电子(中国) death.

Together, these discoveries changed the understanding of JDB电子(中国) death: regulated JDB电子(中国) death is not a single process, but a series of biological events driven by different molecular mechanisms, responding to different intrinsic and extrinsic signals, and carrying different physiological and pathological significance.

However, an important question remains: have we already found all the important modes of JDB电子(中国) death?

The answer is very likely no.

In many human diseases, JDB电子(中国) death is one of the most prominent pathological features. Examples include neuronal loss in neurodegenerative diseases, hepatocyte necrosis in various forms of hepatitis, and renal tubular epithelial JDB电子(中国) death in acute kidney injury.

For a considerable proportion of these JDB电子(中国) death phenomena, we are still accustomed to broadly attributing them to necrosis caused by injury, without necessarily truly understanding the underlying molecular mechanisms.

These unexplained JDB电子(中国) death phenomena may harbor new death programs and may also provide new opportunities for disease intervention.

2. A special compound that left a puzzle unsolved for years

The starting point of this study can be traced back to earlier explorations of noncanonical JDB电子(中国) death in the field of chemical biology.

While studying different types of JDB电子(中国) death, Prof. Scott Dixon and collaborators discovered a class of small-molecule compounds capable of inducing noncanonical JDB电子(中国) death. Among them, the oxime-containing compound CIL56 attracted researchers’ interest.

CIL56 can effectively induce JDB电子(中国) death in certain JDB电子(中国)s, but this process cannot be fully explained by classical apoptosis or other known major JDB电子(中国) death mechanisms.

These early studies suggested that CIL56 may trigger a JDB电子(中国) death process that had not yet been elucidated.

An important breakthrough came from genetic screening.

The Dixon laboratory had previously used a CRISPR screen to identify TECR as being involved in CIL56-induced JDB电子(中国) death, providing an important clue for identifying key molecules in this death process. However, that study did not further clarify how TECR mediates JDB电子(中国) death, nor did it explore whether this process has physiological and pathological significance.

Meanwhile, Dr. Ze Zhang, together with Dr. Xiaoyan Ru and Ph.D. student Xinran Li, started from this unusual chemically induced death phenomenon and independently conducted a genome-wide CRISPR-Cas9 genetic screen to identify key genes determining whether JDB电子(中国)s are sensitive to CIL56.

The screening results likewise brought an unexpected protein to the researchers’ attention: TECR.

TECR (trans-2,3-enoyl-CoA reductase) is an enzyme localized to the endoplasmic reticulum and traditionally considered to participate in the elongation of very-long-chain fatty acids, responsible for the final step of carbon-carbon double-bond reduction.

Its classical function belongs to lipid metabolism and appears to have no direct connection to JDB电子(中国) death.

However, the experimental results were very clear: when researchers knocked out TECR, JDB电子(中国)s became almost completely resistant to CIL56-induced death; re-expression of TECR restored JDB电子(中国)ular sensitivity to CIL56.

A metabolic enzyme originally involved in fatty acid synthesis had unexpectedly become a key protein determining JDB电子(中国) life and death.

How exactly does TECR link lipid metabolism to JDB电子(中国) death?

This question became the core of subsequent research.

3. TECR’s other identity: what determines JDB电子(中国) death is not fatty acid elongation, but protein palmitoylation

The researchers first considered whether, since TECR participates in very-long-chain fatty acid synthesis, loss of TECR alters the lipid composition of JDB电子(中国) membranes and thereby makes JDB电子(中国)s less vulnerable to damage.

This was a seemingly reasonable explanation.

But the experimental results did not support this hypothesis.

The researchers found that the catalytic activity of TECR is essential for inducing JDB电子(中国) death; however, interfering with the classical very-long-chain fatty acid elongation pathway in which it participates did not effectively prevent death.

This seemingly contradictory result suggested that TECR may have a previously unrecognized function.

New clues came from fatty acid synthesis.

Dr. Zhang Ze and colleagues found that inhibiting de novo fatty acid synthesis in JDB电子(中国)s could effectively block CIL56-induced death.

The main end product of de novo fatty acid synthesis in the cytoplasm is the 16-carbon fatty acid palmitate. Palmitate can not only be transported to the endoplasmic reticulum as a substrate for synthesizing longer-chain fatty acids, but can also participate in protein palmitoylation through palmitoyl-CoA.

This discovery led the researchers to a new idea:

Is it not the fatty acid elongation reaction involving TECR that determines JDB电子(中国) death, but rather the palmitoylation of some protein?

And could that protein be TECR itself?

S-palmitoylation is an important post-translational protein modification that attaches palmitate to cysteine residues of proteins via thioester bonds, thereby altering protein localization, interactions, and function.

Through further biochemical experiments, the researchers found that TECR itself can indeed undergo S-palmitoylation, and that this modification is essential for its function in inducing JDB电子(中国) death.

TECR contains seven cysteine residues. Unexpectedly, mutating one or even several of these sites individually was insufficient to completely block death; only simultaneous mutation of all seven sites completely eliminated the detected TECR palmitoylation and the JDB电子(中国) death it mediates.

This result suggested functional redundancy among multiple palmitoylation sites in TECR.

So who is responsible for adding or removing palmitoylation modifications on TECR?

The research team further identified key enzymes regulating this process: ZDHHC5 and its accessory protein GOLGA7, as well as ZDHHC2, participate in TECR palmitoylation; conversely, the depalmitoylase ABHD10 exerts the opposite effect.

Thus, a new regulatory module gradually became clear:

The palmitoylation status of TECR is dynamically controlled by a set of enzymes that add and remove lipid modifications, and determines whether JDB电子(中国)s enter this death program.

This discovery directly links fatty acid metabolism, post-translational protein modification, and JDB电子(中国) death.

More importantly, it revealed a previously unrecognized phenomenon: an enzyme traditionally involved in lipid metabolism can acquire the function of regulating JDB电子(中国) death through its own lipid modification.

4. The endoplasmic reticulum is not only the JDB电子(中国)’s production workshop, but may also become the starting point of death

TECR is mainly localized to the endoplasmic reticulum.

The endoplasmic reticulum is an important site for protein folding, lipid synthesis, and regulation of calcium homeostasis within JDB电子(中国)s. When endoplasmic reticulum function is disturbed, JDB电子(中国)s initiate the endoplasmic reticulum stress response (ER stress) in an attempt to restore normal JDB电子(中国)ular function.

Traditionally, ER stress has been considered an adaptive protective mechanism, but if stress is too severe or persists for too long, it can also lead to JDB电子(中国) death.

So, does TECR palmitoylation initiate death through ER stress?

The researchers observed that after CIL56 treatment, TECR aggregated on the endoplasmic reticulum, accompanied by significant endoplasmic reticulum swelling and structural disruption.

Further analysis revealed that PERK was phosphorylated and activated in these JDB电子(中国)s, followed by phosphorylation of eIF2α and increased expression of ATF4 and CHOP.

These changes suggested that TECR-mediated JDB电子(中国) death is closely associated with ER stress.

However, ER stress includes three major signaling branches: PERK, IRE1α, and ATF6. Which one is responsible for executing death?

The researchers found that inhibiting the PERK signaling pathway significantly protected JDB电子(中国)s, whereas inhibiting IRE1α or ATF6 did not produce similar effects.

These results linked TECR palmitoylation to the PERK–eIF2α signaling pathway, revealing a necrotic JDB电子(中国) death mechanism driven by ER stress.

Unlike known death pathways, this process does not depend on their respective classical death-execution mechanisms.

Thus, the research team established a new JDB电子(中国) death signaling pathway:

TECR palmitoylation → activation of PERK–eIF2α–ATF4–CHOP signaling → necrotic JDB电子(中国) death.

Notably, this does not mean that all ER stress leads to JDB电子(中国) death, nor that PERK is a pro-death factor under all circumstances.

What truly matters is that the study identified a specific death process initiated by TECR palmitoylation and dependent on PERK signaling.

5. From culture dishes to the liver: does this mode of death truly participate in disease?

Discovering a new JDB电子(中国) death mechanism is important, but the more critical question is: does it occur in real physiological and pathological settings?

The research team selected two models of acute liver injury caused by different mechanisms.

The first was Concanavalin A (Con A)-induced immune hepatitis, and the second was drug-induced liver injury caused by acetaminophen (APAP) overdose.

The initiating injury factors in the two models are entirely different: the former is mainly driven by immune responses, while the latter is closely related to toxic injury produced by drug metabolism.

However, both can ultimately lead to severe hepatocyte death, tissue necrosis, and inflammatory responses.

The researchers first found that the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly alleviated liver injury in both models, reduced serum ALT and AST levels, decreased hepatocyte death and inflammatory JDB电子(中国) infiltration, and improved animal survival.

However, 2-BP can affect the palmitoylation of multiple proteins and is not a TECR-specific inhibitor. Therefore, this result alone could not determine whether TECR truly participates in the disease process.

To this end, the research team further generated hepatocyte-specific Tecr knockout mice.

The results showed that in both acute liver injury models, loss of TECR significantly alleviated liver injury and improved animal survival.

This genetic evidence indicates that TECR not only participates in a special death program in cultured JDB电子(中国)s, but also plays an important role in the pathological process of acute liver injury.

At the same time, intervening in PERK–eIF2α-related stress responses also alleviated APAP-induced liver injury, providing further in vivo support for the mechanism revealed by JDB电子(中国) experiments.

From chemical probes to genetic screening, from protein modification to signaling pathways, and then to animal disease models, this study connected a previously underappreciated JDB电子(中国) death mechanism with real organ injury.

This discovery also raises a more eagerly anticipated question:

Since TECR participates in hepatocyte death, could blocking this death process become a new strategy for treating acute liver injury?

6. An exciting finding: can more treatment time be gained for acute liver injury?

Acetaminophen is a widely used antipyretic and analgesic worldwide, but overdose can cause severe acute liver injury and even acute liver failure.

Currently, N-acetylcysteine (NAC) is an important drug for treating acetaminophen poisoning. Its efficacy is closely related to the timing of administration; the earlier it is used, the more effectively it can usually reduce liver injury.

However, in clinical practice, not all patients can receive treatment promptly after poisoning. For patients who have already developed obvious liver injury, how to prevent further hepatocyte death remains an important medical challenge.

The research team therefore proposed a new idea:

If the TECR-mediated death program participates in the progression of liver injury, then even after the initial toxic injury has occurred, can inhibiting this death program still protect the liver?

To seek possible pharmacological interventions, the researchers screened approximately 12,000 small-molecule compounds and identified GNF-5837 as an effective inhibitor of TECR-related JDB电子(中国) death.

GNF-5837 was previously considered a TRK kinase inhibitor, but the researchers found that its protective effect on this death process does not depend on TRK inhibitory activity, suggesting that this compound has a mechanism of action that remains to be further elucidated.

In the APAP-induced mouse model of acute liver injury, the researchers found that even when GNF-5837 was administered 6 hours after injury onset, approximately 60% of the animals still survived.

In contrast, under the experimental conditions used in this study, the effective protection of NAC was mainly observed when it was administered earlier after injury.

This result is encouraging.

The main effect of NAC is to replenish glutathione and help hepatocytes clear the toxic products produced by acetaminophen metabolism, so earlier use is generally more effective. In contrast, GNF-5837 inhibits the JDB电子(中国) death process that occurs after toxic injury.

The two act at different stages of liver injury progression.

This means that even after the initial toxic injury has occurred, blocking the subsequent JDB电子(中国) death program may still rescue hepatocytes that have not yet died.

This discovery raises a concept of important clinical significance: for acute organ injury, therapeutic strategies can target not only the initial pathogenic factor, but also directly intervene in the JDB电子(中国) death process that continues to advance after injury.

Of course, the therapeutic window in animal experiments cannot be directly equated with the clinical therapeutic window in humans. NAC may still have therapeutic value in clinical practice even when administered late. The direct target, drug selectivity, pharmacokinetics, and safety of GNF-5837 also require further study.

But this study at least demonstrates an important possibility: targeting the TECR-related JDB电子(中国) death pathway may provide a new strategy for acute liver injury that differs from traditional detoxification therapy and may potentially expand the effective intervention time window.

7. From a JDB电子(中国) death phenomenon to understanding common mechanisms of organ injury

Over the past decades, JDB电子(中国) death research has undergone a profound transformation from morphological observation to molecular mechanism analysis.

Apoptosis research revealed how the caspase protease cascade determines JDB电子(中国) fate; necroptosis research demonstrated that RIPK3 phosphorylation of the pseudokinase MLKL can initiate plasma membrane rupture; pyroptosis research discovered the death mechanism by which gasdermin proteins form plasma membrane pores; and ferroptosis revealed JDB电子(中国) death caused by uncontrolled iron-dependent lipid peroxidation.

The discovery of the TECR-related death pathway adds a new research direction to this field.

It suggests that a protein traditionally classified as a metabolic enzyme can, under specific conditions, participate in entirely different JDB电子(中国) signaling regulatory processes through its own post-translational modification. The connection between lipid metabolism and JDB电子(中国) death may be far more direct and complex than previously recognized.

At the same time, this study also raises a series of deeper scientific questions.

First, what endogenous signal actually initiates TECR palmitoylation?

The current study used compounds such as CIL56 to reveal this death pathway, but in real diseases, what factors lead to increased TECR palmitoylation remains to be clarified.

Particularly noteworthy is that Con A-induced immune hepatitis and APAP-induced drug-induced liver injury have completely different initial pathogenic mechanisms, yet both show significant dependence on TECR.

Does this mean that different types of liver injury ultimately converge on some common intraJDB电子(中国)ular signal, which then initiates the TECR-mediated death program?

If such a common signal does exist, does it also participate in viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease, or liver injury caused by other reasons?

Second, after TECR palmitoylation, how exactly is PERK activated?

PERK is usually activated by sensing changes in endoplasmic reticulum homeostasis. Does TECR palmitoylation directly alter the local environment of the endoplasmic reticulum membrane, or initiate PERK signaling through as-yet-undiscovered protein interactions? Are there other key death-execution molecules in this process?

The answers to these questions will help researchers further understand the molecular nature of this death pathway.

Finally, TECR is widely expressed in multiple tissues. Is the death program it mediates limited to the liver?

In acute kidney injury, neurodegenerative diseases, and other organ injuries, is there also JDB电子(中国) death driven by TECR palmitoylation? If so, could intervening in this common death mechanism provide new therapeutic strategies for different diseases?

These questions currently have no answers, but they are precisely what makes this discovery most exciting.

The true importance of a new JDB电子(中国) death pathway lies not only in the discovery of a new molecular mechanism, but also in whether it can help us understand disease phenomena that were previously unexplained.

Looking back at the course of this research, from an initially chemically induced death phenomenon that could not be explained by known mechanisms, to the discovery of TECR through genetic screening, and then to the revelation of palmitoylation regulation, PERK signaling activation, and its pathological role in acute liver injury, the researchers gradually developed an isolated JDB电子(中国) biology phenomenon into a molecular mechanism with disease significance and potential therapeutic value.

Scientific discovery often begins with dissatisfaction with existing explanations. If an apparently special experimental phenomenon can be persistently interrogated for its underlying molecular mechanisms, it may reveal biological principles of general significance.

From discovering how JDB电子(中国)s die, to understanding why JDB电子(中国)s die in disease, and then to finding ways to prevent such death—this is precisely the direction in which JDB电子(中国) death research continues to advance.

This study was led by Dr. Ze Zhang at the National Institute of Biological Sciences, Beijing, and the Tsinghua Institute of Multidisciplinary Biomedical Research. Ze Zhang and Xiaodong Wang are co-corresponding authors of the paper. Xiaoyan Ru is the first author. Xinran Li, Zhili Wu, Xinhua Ren, Yu Zong, Yazhong Cui, Yuhua Li, Zhangcheng Ding, and others participated in the research.

The research was supported by funding from relevant agencies of the Ministry of Science and Technology of China and the Beijing Municipal Science & Technology Commission. Ze Zhang was supported by Cancer Research Institute Irvington Postdoctoral Fellowship (USA).