ALDH1A3 (Aldehyde Dehydrogenase 1 Family Member A3)

Our study provides the first evidence that Dioscin inhibits ALDH1A3-mediated RA metabolism and cancer stemness. Our data will further support its potential as a therapeutic agent for cancer treatment.

Notably, demethylation therapy induced sustained complete remission in patients with refractory recurrent APL during experimental treatment. Our findings underscore the critical role of ALDH1A3 in leukemogenesis and highlight its potential as a therapeutic target in APL.

Proteomics investigation of a MSC-transformation model of sarcoma has yielded ALDH1A3 and CD99 as potential targets for sarcomagenesis that may contribute to a greater understanding of the disease and the development of novel therapeutic approaches.

Disrupting this axis induces ferroptotic death and impairs PDAC development. Our study reveals a previously unrecognized mechanism in which HERVH-derived eRNAs regulate ferroptosis via super-enhancer-mediated transcriptional reprogramming and highlights the KLF5/HERVH/ALDH1A3 pathway as a potential therapeutic target in PDAC.

Notably, pharmacological inhibition of ALDH1A3 using 673A effectively disrupted this regulatory circuit and exerts a synergistic effect with gemcitabine in PDX. These findings not only delineate a histone lactylation-driven positive feedback loop sustaining chemoresistance through HNRNPC-mediated autophagy activation, but also develop the potential of 673A as a promising clinical candidate for overcoming gemcitabine resistance in PDAC treatment.

We also highlight major challenges, such as interindividual microbiome variability, potential collateral harm to ferroptosis-sensitive immune cells, adaptive antioxidant compensation (e.g., NRF2/FSP1 activation), and safety/regulatory issues for live biotherapeutics. In summary, this review highlights that targeting the microbiota-ferroptosis axis may represent a rational and potentially transformative approach to reprogramming the tumor microenvironment and overcoming immune checkpoint resistance in pMMR/MSS colorectal cancer; however, further research is essential to validate this concept and address existing challenges.

Further mechanism studies have shown that the transcription factor ONECUT2 is also highly expressed in CRC and indicates a poor prognosis, and it can directly activate its transcription by binding to the ADAMTS14 promoter region. In conclusion, this study has revealed a novel mechanism by which the ONECUT2/ADAMTS14/Wnt axis regulates the stemness of CRC cells, providing a potential molecular target for targeted intervention.

Instead, atRA produced by ALDH1A3 acts in a paracrine fashion to activate retinoid nuclear receptor signaling in immune cells to suppress anti-tumor immunity. To inhibit ALDH1A3, we developed a hybrid in silico and high-throughput screening approach followed by medicinal optimization to identify first-in-class, oral and safe antagonists of ALDH1A3 with potent anti-tumor immunotherapeutic activity and an optimized drug development profile.

Schematic diagram illustrating the mechanism by which SETD7 accelerates ESCC progression through enhancing ferroptosis resistance. Created with BioRender.

To evaluate the association between the p62 and ALDH1A3 expression levels and endocrine therapy, including tamoxifen and aromatase inhibitor, in patients with luminal B breast cancer, disease-specific survival was examined using Kaplan-Meier and multivariate Cox regression analyses...These results suggest that endocrine therapy, especially aromatase inhibitors, exhibits a reduced effectiveness against p62 high ALDH1A3 high luminal B tumors. p62 and ALDH1A3 could be used together as a prognostic biomarker for predicting the efficacy of endocrine therapy for luminal B breast cancer.

PKC ζ and CTNNBIP1 may be involved in the progression of ALDH1A3-positive luminal B breast cancer. In luminal B breast cancer, PKC ζ , CTNNBIP1 and ALDH1A3 could serve as molecular drug targets and prognostic biomarkers to predict the effectiveness of hormone therapy.

ABD0171 disrupted key oncogenic pathways, including IL6/JAK/STAT3, tPA, and Src/FAK, resulting in robust antitumor and antimetastatic effects in vitro and in vivo, with a favorable safety profile. These findings establish ALDH1A3 as a therapeutic target in breast cancers with epithelial-basal traits and validate ABD0171 as a promising clinical candidate to address current treatment challenges.