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Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target. [Display omitted] • Lysosomal cyst(e)ine storage and release maintains GSH levels for ROS buffering • MFSD12 is phosphorylated by mTORC1 at T254 to control lysosomal cyst(e)ine storage • MFSD12-T254A mutant acts as a dominant-negative inhibitor of MFSD12 functions • MFSD12 upregulation induces chemoresistance and poor prognosis in breast cancer He et al. report that MFSD12 upregulation in breast cancer increases the lysosomal cyst(e)ine storage, providing a ready source of cyst(e)ine for GSH synthesis, which is regulated by mTORC1 to fine-tune redox homeostasis and enhance cell fitness. [ABSTRACT FROM AUTHOR]

Acephalic spermatozoa syndrome is a severe teratozoospermia that leads to male infertility. Our previous work showed that biallelic SUN5 mutations are responsible for acephalic spermatozoa syndrome in about half of affected individuals, while pathogenic mechanisms in the other individuals remain to be elucidated. Here, we identified a homozygous nonsense mutation in the testis-specific gene PMFBP1 using whole-exome sequencing in a consanguineous family with two infertile brothers with acephalic spermatozoa syndrome. Sanger sequencing of PMFBP1 in ten additional infertile men with acephalic spermatozoa syndrome and without SUN5 mutations revealed two homozygous variants and one compound heterozygous variant. The disruption of Pmfbp1 in male mice led to infertility due to the production of acephalic spermatozoa and the disruption of PMFBP1’s cooperation with SUN5 and SPATA6, which plays a role in connecting sperm head to the tail. PMFBP1 mutation-associated male infertility could be successfully overcome by intracytoplasmic sperm injection (ICSI) in both mouse and human. Thus, mutations in PMFBP1 are an important cause of infertility in men with acephalic spermatozoa syndrome. [ABSTRACT FROM AUTHOR]

The zona pellucida (ZP) is an extracellular glycoprotein matrix surrounding mammalian oocytes. Recently, numerous mutations in genes encoding ZP proteins have been shown to be possibly related to oocyte abnormality and female infertility; few reports have confirmed the functions of these mutations in living animal models. Here, we identified a novel heterozygous missense mutation (NM_001376231.1:c.1616C>T, p.Thr539Met) in ZP2 from a primary infertile female. We showed that the mutation reduced ZP2 expression and impeded ZP2 secretion in cell lines. Furthermore, we constructed the mouse model with the mutation ( Zp2 T541M ) using CRISPR-Cas9. Zp2 WT/T541M female mice had normal fertility though generated oocytes with the thin ZP, whereas Zp2 T541M female mice were completely infertile due to degeneration of oocytes without ZP. Additionally, ZP deletion impaired folliculogenesis and caused female infertility in Zp2 T541M mice. Our study not only expands the spectrum of ZP2 mutation sites but also, more importantly, increases the understanding of pathogenic mechanisms of ZP2 mutations., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Metastasis in cervical cancer (CC) has a significant negative impact on patient survival, highlighting the urgent need for investigation in this area. In this study, we identified significant overexpression of zinc finger, X-linked, duplicated family member C ( ZXDC ) in CC tissue with metastasis, which correlates with poor outcomes for CC patients. We observed that overexpression of ZXDC promotes, while silencing of ZXDC inhibits the metastasis of CC cells both in vitro and in vivo . Additionally, our research demonstrated that ZXDC activated RhoA / ROCK signaling pathway, leading to enhanced cytoskeleton remodeling in CC cells. Besides, we found that IGF2BP3 plays an essential role in the activation of ZXDC on the RhoA / ROCK signaling pathway by stabilizing RhoA mRNA. These findings reveal a mechanism whereby ZXDC promotes the cervical cancer metastasis by targeting IGF2BP3 / RhoA / ROCK pathway., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Alternative splicing (AS) is a critical mechanism for the aberrant biogenesis of long non-coding RNA (lncRNA). Although the role of Wnt signaling in AS has been implicated, it remains unclear how it mediates lncRNA splicing during cancer progression. Herein, we identify that Wnt3a induces a splicing switch of lncRNA-DGCR5 to generate a short variant (DGCR5-S) that correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). Upon Wnt3a stimulation, active nuclear β-catenin acts as a co-factor of FUS to facilitate the spliceosome assembly and the generation of DGCR5-S. DGCR5-S inhibits TTP's anti-inflammatory activity by protecting it from PP2A-mediated dephosphorylation, thus fostering tumor-promoting inflammation. Importantly, synthetic splice-switching oligonucleotides (SSOs) disrupt the splicing switch of DGCR5 and potently suppress ESCC tumor growth. These findings uncover the mechanism for Wnt signaling in lncRNA splicing and suggest that the DGCR5 splicing switch may be a targetable vulnerability in ESCC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)