The SLC39A1-DRP1 axis: A paradigm shift in targeting mitochondrial dynamics for HCC therapy

Abstract

No abstract available

Hepatocellular carcinoma (HCC) remains a formidable global health challenge, with recurrence rates exceeding 70% post-resection due to elusive molecular drivers.^{1, 2} The groundbreaking study by Li et al. (CTM2-2024-12-4200) unveils the SLC39A1-DRP1 interaction as a linchpin in HCC recurrence, bridging mitochondrial dysfunction to therapeutic innovation.³ Here, we distil the study's transformative insights and their implications for precision oncology.

SLC39A1, traditionally known for zinc transport, emerges as an oncogenic disruptor of mitochondrial quality control. Li et al. demonstrate that SLC39A1 hyperactivates DRP1, triggering aberrant fission, mitophagy, and ROS suppression—key survival mechanisms for residual HCC cells. Strikingly, this effect is zinc—independent, challenging dogma and revealing a moonlighting role for SLC39A1 in mitochondrial dynamics. The study's multi-omics rigor—spanning clinical cohorts (n = 27), TCGA validation, and genetically engineered mice—solidifies SLC39A1 as a prognostic biomarker and actionable target.

The study's crowning achievement is a rationally designed peptide that disrupts SLC39A1-DRP1 binding, restoring mitochondrial homeostasis and inducing apoptosis in preclinical models. This approach outshines broad-spectrum inhibitors by precision-targeting a nodal interaction, minimizing off-target effects. The peptide's efficacy in xenografts underscores its potential as an adjuvant therapy to curb post-surgical recurrence—a critical unmet need.

Previous work by Bao et al.⁴ established that DRP1-mediated mitochondrial fission promotes cancer metastasis through cytosolic mtDNA release and TLR9/NF-κB pathway activation, a mechanism that aligns with and strengthens Li et al.’s observations of DRP1's pro-tumorigenic role in HCC. While SLC39A1 has been primarily characterized as a zinc transporter involved in maintaining cellular zinc homeostasis,⁵ this study uncovered a zinc-independent oncogenic mechanism, significantly expanding our understanding of its functional diversity in cancer progression. However, several key controversies and knowledge gaps emerge when situating these findings within the larger literature. The role of autophagy in cancer remains particularly contentious—while previous study demonstrated tumour-suppressive effects through p62/SQSTM1-mediated pathways,⁶ Li et al.’s data suggest SLC39A1-induced autophagy promotes HCC recurrence, potentially indicating stage- or context-dependent functionality. This paradox is further complicated by tissue-specific differences in SLC39A1 activity. Notably, in prostate cancer models, SLC39A1 exhibits tumour-suppressive properties by inhibiting NF-κB signalling,⁷ starkly contrasting with its pro-tumorigenic role in HCC. These discrepancies underscore the critical importance of considering tissue context and disease stage when evaluating the therapeutic potential of targeting the SLC39A1-DRP1 pathway, and highlight the need for further research to elucidate the molecular determinants of these context-dependent effects. The study's revelation of zinc-independent mechanisms also challenges existing paradigms about SLC39A1's primary functions, suggesting that its role in mitochondrial dynamics may represent a previously underappreciated aspect of its contribution to oncogenesis.

While this study provides compelling evidence for the role of SLC39A1-DRP1 interaction in HCC recurrence, several limitations and unresolved questions merit consideration. The clinical cohort size (n = 27)—while sufficient for initial discovery—remains relatively modest, highlighting the need for larger, multi-centre validation studies to strengthen the statistical power and generalizability of these findings. Additionally, while the study establishes SLC39A1's influence on DRP1-mediated mitochondrial fission, the precise molecular mechanisms—particularly regarding potential post-translational modifications like DRP1 phosphorylation at Ser616 that may be regulated by SLC39A1–require deeper investigation to fully elucidate the signalling cascade. Perhaps most intriguing is the unexpected finding that SLC39A1's oncogenic effects appear zinc-independent, despite its well-characterized function as a zinc transporter. This observation contradicts previous studies demonstrating zinc's crucial role in immune modulation (particularly Th1/Th2 balance) and creates a paradox that demands resolution. The disconnect between SLC39A1's zinc transport capability and its newly identified role in mitochondrial dynamics suggests either: (1) the existence of novel, zinc-independent functions of SLC39A1 in cancer progression, or (2) more complex zinc signalling pathways that were not captured in the current experimental design. These unresolved questions not only highlight important gaps in our understanding of SLC39A1 biology but also underscore the need for more comprehensive studies examining potential context-dependent differences in its mechanisms of action across various cancer types and microenvironments.

The study's findings open several promising translational and research avenues for improving HCC management. For therapeutic development, optimizing the stability and bioavailability of the SLC39A1-targeting peptide through nanoparticle encapsulation or other drug delivery systems could significantly enhance its clinical potential as an adjuvant therapy to prevent post-surgical recurrence. Furthermore, combining DRP1 inhibitors like Mdivi-1 with existing immunotherapies (e.g., anti-PD1 checkpoint inhibitors) may create synergistic treatment strategies that simultaneously target mitochondrial dynamics and immune evasion mechanisms. Deeper mechanistic investigations using cryo-electron microscopy could elucidate the structural details of the SLC39A1-DRP1-MCU complex, potentially revealing novel druggable pockets for more precise pharmacological intervention. Additionally, exploring how SLC39A1 influences the tumour microenvironment—particularly its effects on tumour-associated macrophages (TAMs) polarization and neutrophil recruitment—could uncover important immune-metabolic cross-talk pathways that contribute to HCC progression. On the diagnostic front, developing liquid biopsy approaches to detect SLC39A1/DRP1 expression levels or mitochondrial DNA fragments in circulation may enable non-invasive monitoring of recurrence risk and treatment response, addressing a critical clinical need for better prognostic tools in HCC management. These multifaceted research directions, spanning from molecular therapeutics to clinical diagnostics, collectively build upon the study's core findings while addressing key gaps in both our biological understanding and clinical capabilities for HCC.

Li et al.’s study establishes the SLC39A1-DRP1 axis as a pivotal regulator of mitochondrial quality control in HCC recurrence, with significant therapeutic potential. While tissue-specific functions and zinc-independent mechanisms pose intriguing questions, the findings pave the way for precision medicine strategies. Future research should prioritize clinical translation, leveraging structural insights and combination therapies to improve patient outcomes.