Acyl-CoA synthetase long-chain family member 4 (ACSL4)

Overview

Acyl-CoA synthetase long chain family member 4 (ACSL4) is a long-chain acyl-CoA synthetase that has emerged as an important regulator of lipid metabolism and ferroptosis. In biomedical research, ACSL4 is commonly discussed as a pro-ferroptotic factor because it contributes to the remodeling of membrane phospholipids with polyunsaturated fatty acids, thereby increasing susceptibility to lipid peroxidation. As a result, ACSL4 is frequently studied in cancer biology, metabolic disease, and ischemia-reperfusion injury, where altered ferroptotic signaling can influence cell survival, tissue damage, and treatment response.

Recent studies have placed ACSL4 within broader redox and lipid-metabolic networks involving GPX4, SLC7A11, Nrf2, HO-1, TFR1, and related inflammatory mediators. In these contexts, ACSL4 is not typically treated as a standalone biomarker, but as part of a mechanistic axis that links iron handling, glutathione depletion, oxidative stress, and membrane lipid damage. This makes ACSL4 a recurring target in experimental work on ferroptosis modulation across liver disease, reproductive toxicity, cerebral ischemia, and multiple cancer models.

Recent Publications Summary

ACSL4 emerges across these reports as the principal pro-ferroptotic lipid-remodeling enzyme whose expression, stability, and catalytic activity determine whether a cell tolerates or succumbs to lipid peroxidation, and much of the recent work is devoted to controlling it pharmacologically or through post-translational regulation. A dual-function PROTAC, dACSL4, was engineered to selectively degrade ACSL4 while simultaneously activating PPARγ, coupling lipid metabolic control to oxidative stress defense; the degrader conferred up to 30-fold greater protection against neuronal ferroptosis than conventional ferroptosis inhibitors, and intranasal delivery in biodegradable BAmP-TK12 lipid nanoparticle achieved brain-preferred ACSL4 degradation, reduced lipid peroxidation, preserved dopaminergic neurons, and improved motor function in a Parkinson's disease model 42480533Jul. A complementary post-translational mechanism was defined in glucocorticoid-induced osteoporosis, where Parkin was shown to bind ACSL4 directly and promote its K48-linked polyubiquitination and proteasomal degradation; Parkin was downregulated in disease models, its knockdown worsened dexamethasone-induced lipid peroxidation, iron accumulation, and mitochondrial dysfunction, and bone-targeted DSS6-modified lipid nanoparticle delivering Parkin mRNA restored osteogenic differentiation and improved bone microstructure in vivo 42439361Jul. In the opposite direction, S-palmitoylation of ACSL4 at cysteine 595 by the palmitoyltransferase ZDHHC9 — itself driven by PI3K/AKT hyperactivation — enhanced ACSL4 enzymatic activity and drove ferroptosis in corpus cavernosum fibroblasts in diabetes mellitus-induced erectile dysfunction, with siZdhhc9 lipid nanoparticle tested as a countermeasure 42085610May.

A second cluster examines ACSL4 as a readout and effector of ferroptosis in ischemic, inflammatory, and environmental injury. salvianolic acid B protected against reperfusion-induced microvascular damage after middle cerebral artery occlusion by suppressing the pro-ferroptotic mediators ACSL4 and TFR1 while promoting Nrf2 nuclear translocation and upregulating heme oxygenase 1 and GPX4, reducing infarct volume, iron deposition, lipid peroxidation, and neuroinflammation, with the Nrf2 inhibitor ML385 used to establish pathway dependence 42186809May. In ulcerative colitis, ACSL4-mediated ferroptosis was positioned within an MTDH/ACSL4/NF-κB axis, and dexamethasone-loaded hollow mesoporous silica nanoparticles combined with ultrasound-targeted microbubble destruction were evaluated for targeted delivery and synergistic therapeutic effect 41791486Mar. PM2.5-aggravated asthma was traced to a Fra2/LCN2 transcriptional axis that induces ferroptosis in M2 macrophages, validated with macrophage-specific LCN2 knockdown via AAV9 and integrated multi-omics, ChIP-qPCR, and mitochondrial integrity assays 42214888May. Neuronal ferroptosis also featured in brain aging, where deficiency of the phospholipid flippase ATP11B promoted Fe²⁺ transfer from ependymal cells to hippocampal neurons, activating Hippo signaling and impairing mitochondrial respiration and quality control to accelerate aging phenotypes and cognitive decline 42002550Apr.

In oncology, ACSL4 upregulation is consistently reported as part of the mechanism by which drugs restore ferroptotic vulnerability. Schisandrin B inhibited pancreatic cancer cell proliferation dose-dependently and induced ferroptosis, with RNA sequencing and KEGG enrichment implicating the ferroptosis pathway and DARTS, molecular docking, and siRNA transfection used for target engagement, with efficacy confirmed in subcutaneous xenograft and orthotopic genetically engineered mouse models 42318966Jun. Combined paclitaxel and sunitinib synergistically inhibited lung tumor growth by concurrently downregulating the ferroptosis suppressors FTH1, GPX4, and SLC7A11 while upregulating ACSL4, producing iron accumulation, glutathione depletion, and lethal lipid peroxidation, with SLC7A11 identified as the critical determinant of response 41955701Apr. In castration-resistant prostate cancer, loss of decorin drove enzalutamide resistance by suppressing ACSL4-dependent lipid remodeling and ferroptosis; decorin was reduced in high-grade tumors and poor-survival cohorts, and its re-expression resensitized enzalutamide-resistant LNCaP cells and suppressed tumor growth and metastasis in a ferroptosis-dependent manner 41861540Mar. Broader inhibition of long-chain acyl-CoA synthetases was pursued in neurofibroma with a pH-responsive silver nanoparticle carrier for Triacsin C, which selectively impaired growth, migration, and invasion of selumetinib-resistant cells while sparing normal Schwann cells and inhibited xenograft growth with good biocompatibility 42177691May.

Finally, computational work places ACSL4 within the ferroptosis gene signature of neurodegeneration: an analysis of early-onset Alzheimer's disease identified six differentially expressed ferroptosis-related genes, narrowed these to four key biomarker candidates by machine learning, and built a neural network diagnostic model reaching an AUC of 0.92, reinforcing the proposed molecular link between iron accumulation, lipid peroxidation, and Alzheimer's neurodegeneration 42474555Jul. Taken together, these studies converge on ACSL4 as a bidirectional therapeutic node — one to be degraded, ubiquitinated, or enzymatically restrained in degenerative and inflammatory disease, and one to be induced or de-repressed to overcome drug resistance in cancer — with lipid nanoparticle, nanoparticle, and ultrasound-assisted delivery platforms recurring as the means of achieving tissue-selective control.

What Changes, What Holds

1. ACSL4 is now being treated as a druggable control point for ferroptosis rather than only a marker of susceptibility
NEW DIRECTION The new work moves ACSL4 beyond the Overview’s role as a pro-ferroptotic lipid-remodeling factor and shows that its degradation, ubiquitination, or enzymatic blockade can be engineered as therapy, especially for neurodegeneration and bone loss 42480533Jul42439361Jul. That does not displace the established mechanism, but it does broaden ACSL4 from a mechanistic node to a direct intervention target, with post-translational control emerging as a major lever.

2. ACSL4 remains a central ferroptosis effector, but the new studies extend its relevance into injury settings and upstream inflammatory control
REINFORCES These reports fit the baseline account that ACSL4 sits within redox and lipid-peroxidation networks, because they again place it alongside Nrf2, GPX4, TFR1, and inflammatory signaling in ischemic and mucosal injury 42186809May41791486Mar. The added value is contextual rather than conceptual: ACSL4 is confirmed as part of the same ferroptotic axis, not recast into a different biology.

3. ACSL4 is being used to explain why some Cancers regain ferroptotic sensitivity, but the direction of use is unchanged
REINFORCES The oncology findings sharpen the baseline view that ACSL4 participates in treatment response and ferroptosis modulation, because increased ACSL4 again accompanies drug-induced vulnerability rather than contradicting it 42318966Jun41955701Apr. Even the resistance example still depends on the same principle: loss of ACSL4-linked lipid remodeling weakens ferroptosis, so restoring that axis can resensitize tumors. The new work adds examples, not a new role.

4. ferroptosis gene signatures may help diagnose neurodegeneration, but this does not yet make ACSL4 a validated biomarker
NEW DIRECTION Computational Alzheimer’s work extends the Overview’s mechanistic link between ACSL4-related ferroptosis and neurodegeneration into a diagnostic setting, but the baseline explicitly says ACSL4 is not typically treated as a standalone biomarker 42474555Jul. Because the paragraph concerns a broader gene signature rather than ACSL4 alone, it suggests a possible translational use while leaving ACSL4’s biomarker status unsettled. The main change is methodological and inferential, not a settled clinical reclassification.

Overview update candidates: ACSL4 as a direct therapeutic target via degradation/ubiquitination/enzymatic inhibition; possible inclusion in ferroptosis-based diagnostic signatures for neurodegeneration; though not as a standalone biomarker.